Monoamine reuptake inhibitors

ABSTRACT

The invention provides bupropion analog compounds capable of inhibiting the reuptake of one or more monoamines. The compounds may selectively bind to one or more monoamine transporters, including those for dopamine, norepinephrine, and serotonin. Such compounds may be used to treat conditions that are responsive to inhibition of the reuptake of monoamines, including addiction, depression, and obesity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international application numberPCT/US2010/031230, filed Apr. 15, 2010, which claims priority to U.S.Provisional Patent Application No. 61/169,586, filed Apr. 15, 2009, bothof which are incorporated herein by reference in their entirety and forall purposes.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with United States Government support underR01DA12970 and N01DA18815, awarded by the National Institute of Health.The United States Government has certain rights in the invention.

FIELD OF THE INVENTION

The present application is directed to various compounds and methods ofpreparation of compounds that are capable of functioning as monoaminereuptake inhibitors. The application is also directed to pharmaceuticalcompositions containing one or more monoamine reuptake inhibitors, whichmay also contain one or more additional therapeutic agents. It is alsodirected to methods of treatment of various conditions that may beresponsive to inhibition of monoamine reuptake, such as addiction anddepression.

BACKGROUND OF THE INVENTION

Drug abuse and addiction are significant medical problems in the UnitedStates. According to the 2007 National Survey on Drug Use and Health, areported 19.9 million Americans aged 12 or older were current illicitdrug users, meaning that they had used an illicit drug during the monthprior to the survey. This estimate represents 0.8 percent of thepopulation aged 12 years old or older. An estimated 3.2 million wereclassified with dependence on or abuse of both alcohol and illicitdrugs, and 3.7 million were dependent on or abused illicit drugs but notalcohol.

Cocaine has one of the highest rates of abuse, and the annual number ofnew cocaine users continues to steadily increase. In 2007, there were2.1 million current cocaine users aged 12 or older. Cocaine is apowerfully addictive drug, often leading to severe medical complicationsincluding cardiovascular effects, such as disturbances in heart rhythmand heart attacks; respiratory effects such as chest pain andrespiratory failure; neurological effects, including strokes, seizures,and headaches; and gastrointestinal complications, such as abdominalpain and nausea. In addition to its direct effects, cocaine abuse hasalso contributed to the increase of the spread of human immunodeficiencyvirus (HIV) infection and drug-resistant tuberculosis. As a result,considerable effort has been devoted to the development of apharmacotherapy to treat patients addicted to cocaine; however, noeffective medication is yet available for use in the clinic.

Indirect dopamine agonists have been postulated to be a class ofcompounds that may show promise for the treatment of cocaine addiction.Studies directed toward the development of indirect dopamine agonistshave involved structurally diverse classes of compounds includinganalogues of 3-phenyltropane, 1,4-dialkylpiperazines, phenylpiperidine,benztropine, methylphenidate, and mazindol.

Bupropion ((±)-2-tert-butylamino-3′-chloropropiophenone, Wellbutrin®) isa well-known antidepressant that has been widely used for the past 30years. Although the neurochemical mechanisms underlying its action stillare not well defined, bupropion is thought to function, at least inpart, as an indirect dopamine agonist. It is known to inhibit thereuptake of dopamine (DA) and norepinephrine (NE) but, unlike many otherantidepressants, has very little effect on serotonin (5HT) reuptake. Itsantidepressant effects have been attributed to its effects on thenoradrenergic system, but some reports suggest that bupropion is morepotent as a DA reuptake inhibitor than an NE reuptake inhibitor.Microdialysis studies have shown that acute bupropion administrationincreases extracellular DA. In behavioral pharmacology studies,bupropion has been shown to induce locomotor activity, generalize tococaine and amphetamine in drug discrimination (DS) studies, producecondition place preference (CPP), and is self-administered in both ratsand non-human primates. In addition, bupropion has been reported toincrease response on a fixed interval (FI) schedule stimulus-shocktermination study in squirrel monkeys. These studies appear todemonstrate bupropion's action as a DA reuptake inhibitor and, thus,indicate that bupropion has the properties of an indirect dopamineagonist.

Bupropion has shown efficacy in addiction. It has been formulated in asustained release formulation for nicotine addiction and is currentlymarketed for this purpose as Zyban®. In a clinical trial of bupropionfor cocaine abuse, an exploratory analysis suggested that patients withdepression may have benefited. Another clinical study has evaluatedbupropion-augmented contingency management for cocaine dependence inmethadone-maintained patients, finding that the combination ofcontingency management with bupropion treatment may successfully reducecocaine use, although there was no evidence for efficacy of bupropionalone. Bupropion has also been studied as a treatment formethamphetamine dependence. In one study, bupropion reducedmethamphetamine-induced subjective effects and cue-induced craving. Inanother study, treatment with bupropion reduced methamphetamine use inrelatively light users.

Although bupropion is a successful treatment for both depression andnicotine addiction, relatively few chemical analogues have been preparedand evaluated. Structural analogues of bupropion that function by thesame mechanisms of action may be successful in treating depression andnicotine addiction, as well as possibly other related diseases,including addictions of other types and obesity.

SUMMARY OF THE INVENTION

The present invention provides compounds useful as monoamine reuptakeinhibitors and methods of synthesis of such compounds. It also providespharmaceutical compositions containing the compounds, which may beuseful in the treatment of various conditions or disorders that may beresponsive to the inhibition of monoamine reuptake by cells. Theinvention further provides methods of treating such conditions anddisorders, including but not limited to, depression and addiction. Forexample, in one aspect, the invention is directed to a method oftreating a condition comprising administering to a subject in need oftreatment of the condition a pharmaceutical composition comprising atherapeutically effective amount of a compound of the present inventionor a pharmaceutically acceptable ester, amide, salt, solvate, prodrug,or isomer thereof.

Accordingly, in one aspect, the present invention provides a compoundthat inhibits the reuptake of one or more monoamines. In someembodiments, the invention provides a compound according to thefollowing structure:

wherein:

R₁-R₅ are each independently selected from H, OH, optionally substitutedC1-4 alkyl, optionally substituted C1-3 alkoxy, optionally substitutedC2-4 alkenyl, optionally substituted C2-4 alkynyl, halogen, amino,acylamido, CN, CF₃, NO₂, N₃, CONH₂, CO₂R₁₂, CH₂OR₁₂, NR₁₂R₁₃, NHCOR₁₂,NHCO₂R₁₂, CONR₁₂R₁₃; C1-3 alkylthio, R₁₂SO, R₁₂SO₂, CF₃S, and CF₃SO₂;

R₆ and R₇ are each independently selected from H or optionallysubstituted C1-10alkyl, or R₆ and R₇ together constitute ═O or ═CH₂;

R₈ and R₉ are each independently selected from H or optionallysubstituted C1-10alkyl;

R₁₀, R₁₁, R₁₂, and R₁₃ are each independently selected from H oroptionally substituted C1-10 alkyl;

and wherein R₁ and R₈ may be joined to form a cyclic ring; or apharmaceutically acceptable ester, amide, salt, solvate, prodrug, orisomer thereof,

with the proviso that when one of R₈ and R₉ is CH₃, then at least one ofR₁₀ and R₁₁ is optionally substituted C3-C10 cycloalkyl.

In some aspects, the invention provides a compound of Formula I, whereinone of R₁₀ and R₁₁ is H and the other of R₁₀ and R₁₁ is optionallysubstituted C3-10 cycloalkyl. In certain aspects, the C3-10 cycloalkylis selected from cyclopropyl, cyclobutyl, and cyclopentyl. In someaspects, the invention provides a compound of Formula I, wherein one ofR₁₀ and R₁₁ is H and the other of R₁₀ and R₁₁ is optionally substitutedtert-butyl.

In some aspects, the invention provides a compound of Formula I, whereinone or both of R₈ and R₉ are C2-C7 alkyl. In certain aspects, one of R₈and R₉ is C2-C7 alkyl and the other of R₈ and R₉ is H. For example, insome aspects, the C2-C7 alkyl is selected from the group consisting ofethyl, propyl, butyl, hexyl, or isobutyl.

In some aspects, the invention provides a compound of Formula I, whereinone or more of R₁, R₂, R₃, R₄, or R₅ is a substituent other than H. Forexample, in certain aspects, the substituent comprises halo, and inparticular embodiments, comprises chloro. Further, in certain aspects,R₆ and R₇ together constitute ═O.

In certain aspects, the invention provides a compound selected from2-(N-cyclopropylamino)-3′-chloropropiophenone,2-(N-cyclopropylamino)-3′-chlorobutyrophenone,2-(N-cyclopropylamino)-3′-chloropentanophenone,2-(N-cyclobutylamino)-3′-chloropropiophenone,2-(N-cyclopentylamino)-3′-chloropropiophenone,2-(N-tert-butylamino)-3′-chlorobutyrophenone;2-(N-tert-butylamino)-3′,4′-dichlorobutyrophenone;2-(N-tert-butylamino)-3′-chloropentanophenone;2-(N-tert-butylamino)-3′,4′-dichloropentanophenone;2-(N-tert-butylamino)-3′-chlorohexanophenone;2-(N-tert-butylamino)-3′-chloroheptanophenone;2-(N-tert-butylamino)-3′-chlorooctanophenone; and2-(N-tert-butylamino)-3′-chlorophenyl-4-methylpentanophenone.

In another aspect of the invention is provided a method for treating ordelaying the progression of disorders that are alleviated by inhibitingmonoamine reuptake in a patient, the method comprising administering atherapeutically effective amount of at least one compound of Formula I.The disorder for which treatment is administered may be, but is notlimited to, the group consisting of addiction, depression, obesity,bipolar disorder, attention deficit disorder (ADD),attention-deficit/hyperactivity disorder (ADHD), hypoactive sexualdesire disorder, antidepressant-induced sexual dysfunction, orgasmicdysfunction, seasonal affective disorder/winter depression, mania,bulimia and other eating disorders, panic disorders, obsessivecompulsive disorder, schitzophrenia, schitzo-affective disorder,Parkinson's disease, narcolepsy, anxiety disorders, insomnia, chronicpain, migraine headaches, and restless legs syndrome. In particular, themethod may relate to treatment for addiction to cocaine,methamphetamine, or nicotine.

In a further aspect of the invention is provided a pharmaceuticalcomposition comprising a compound according to Formula I and apharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter withreference to the accompanying drawings, in which some, but not allembodiments of the inventions are shown. Indeed, these inventions may beembodied in many different forms and should not be construed as limitedto the embodiments set forth herein; rather, these embodiments areprovided so that this disclosure will satisfy applicable legalrequirements. As used in the specification, and in the appended claims,the singular forms “a”, “an”, “the”, include plural referents unless thecontext clearly dictates otherwise.

The present invention provides compounds that may function as monoaminereuptake inhibitors, as well as methods of preparation andpharmaceutical compositions thereof. It also provides methods for usingsuch compounds to treat a variety of disorders that may be responsive tothe inhibition of monoamine reuptake. In particular, the compositionsand methods can be used in the treatment of various drug addictions,depression, and obesity. Treatment can comprise the use of a compound ofthe present invention as a single active agent. In other embodiments,treatment can comprise the use of a compound of the present invention incombination with one or more further active agents. The specificpharmaceutical composition (or compositions) used in the invention, andthe methods of treatment provided by the invention, are furtherdescribed below.

DEFINITIONS

The term “alkyl” as used herein means saturated straight, branched, orcyclic hydrocarbon groups (i.e., cycloalkyl). In particular embodiments,alkyl refers to groups comprising 1 to 10 carbon atoms (“C1-10 alkyl”).In further embodiments, alkyl refers to groups comprising 1 to 8 carbonatoms (“C1-8 alkyl”), 1 to 6 carbon atoms (“C1-6 alkyl”), or 1 to 4carbon atoms (“C1-4 alkyl”). In other embodiments, alkyl refers togroups comprising 3-10 carbon atoms (“C3-10 alkyl”), 3-8 carbon atoms(“C3-8 alkyl”), or 3-6 carbon atoms (“C3-6 alkyl”). In specificembodiments, alkyl refers to methyl, trifluoromethyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl,isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl,3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

The term “optionally substituted” refers to moieties optionallycontaining one or more distinct substituent groups therein, such as oneor more of the following substituent groups: halo (e.g., Cl, F, Br, andI); halogenated alkyl (e.g., CF₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, orCF₂CF₃; hydroxyl; amino; carboxylate; carboxamido; alkylamino;arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid;sulfate; phosphonic acid; phosphate; and phosphonate.

The term “alkenyl” as used herein means alkyl moieties wherein at leastone saturated C—C bond is replaced by a double bond. In particularembodiments, alkenyl refers to groups comprising 2 to 10 carbon atoms(“C2-10 alkenyl”). In further embodiments, alkenyl refers to groupscomprising 2 to 8 carbon atoms (“C2-8 alkenyl”), 2 to 6 carbon atoms(“C2-6 alkenyl”), or 2 to 4 carbon atoms (“C2-4 alkenyl”). In specificembodiments, alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl.

The term “alkynyl” as used herein means alkyl moieties wherein at leastone saturated C—C bond is replaced by a triple bond. In particularembodiments, alkynyl refers to groups comprising 2 to 10 carbon atoms(“C2-10 alkynyl”). In further embodiments, alkynyl refers to groupscomprising 2 to 8 carbon atoms (“C2-8 alkynyl”), 2 to 6 carbon atoms(“C2-6 alkynyl”), or 2 to 4 carbon atoms (“C2-4 alkynyl”). In specificembodiments, alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl.

The term “alkoxy” as used herein means straight or branched chain alkylgroups linked by an oxygen atom (i.e., —O-alkyl), wherein alkyl is asdescribed above. In particular embodiments, alkoxy refers tooxygen-linked groups comprising 1 to 10 carbon atoms (“C1-10 alkoxy”).In further embodiments, alkoxy refers to oxygen-linked groups comprising1 to 8 carbon atoms (“C1-8 alkoxy”), 1 to 6 carbon atoms (“C1-6alkoxy”), 1 to 4 carbon atoms (“C1-4 alkoxy”) or 1 to 3 carbon atoms(“C1-3 alkoxy”).

The term “halo” or “halogen” as used herein means fluorine, chlorine,bromine, or iodine.

The term “alkylthio” as used herein means a thio group with one or morealkyl substituents, where alkyl is defined as above.

The term “acylamido” refers to an amide group with one or more acylsubstituents, where acyl is as defined below.

The term “acyl” as used herein means a group that can be represented byC(═O)R, in which R is selected from H, alkyl; alkoxy; alkoxyalkylincluding methoxymethyl; aralkyl including optionally substitutedbenzyl; aryloxyalkyl such as phenoxymethyl; aryl including phenyloptionally substituted with halogen, C1-C6 alkyl or C1-C6 alkoxy;sulfonate esters such as alkyl or aralkyl sulphonyl includingmethanesulfonyl; amino, mono-, di-, or triphosphate ester; trityl ormonomethoxytrityl; trialkylsilyl such as dimethyl-t-butylsilyl ordiphenylmethylsilyl.

The terms “aralkyl” and “arylalkyl” as used herein mean an aryl group asdefined above linked to the molecule through an alkyl group as definedabove.

The terms “alkaryl” and “alkylaryl” as used herein means an alkyl groupas defined above linked to the molecule through an aryl group as definedabove.

The term “amino” as used herein means a moiety represented by thestructure NR₂, and includes primary amines, and secondary and tertiaryamines substituted by alkyl (i.e., alkylamino). Thus, R₂ may representtwo hydrogen atoms, two alkyl moieties, or one hydrogen atom and onealkyl moiety.

The term “cycloalkyl” means a non-aromatic, monocyclic or polycyclicring comprising carbon and hydrogen atoms.

The term “aryl” as used herein means a stable monocyclic, bicyclic, ortricyclic carbon ring of up to 8 members in each ring, wherein at leastone ring is aromatic as defined by the Hückel 4n+2 rule. Exemplary arylgroups according to the invention include phenyl, naphthyl,tetrahydronaphthyl, and biphenyl.

The term “analogue” as used herein means a compound in which one or moreindividual atoms or functional groups have been replaced, either with adifferent atom or a different functional, generally giving rise to acompound with similar properties.

The term “derivative” as used herein means a compound that is formedfrom a similar, beginning compound by attaching another molecule or atomto the beginning compound. Further, derivatives, according to theinvention, encompass one or more compounds formed from a precursorcompound through addition of one or more atoms or molecules or throughcombining two or more precursor compounds.

The term “prodrug” as used herein means any compound which, whenadministered to a mammal, is converted in whole or in part to a compoundof the invention.

The term “active metabolite” as used herein means a physiologicallyactive compound which results from the metabolism of a compound of theinvention, or a prodrug thereof, when such compound or prodrug isadministered to a mammal.

The terms “therapeutically effective amount” or “therapeuticallyeffective dose” as used herein are interchangeable and mean aconcentration of a compound according to the invention, or abiologically active variant thereof, sufficient to elicit the desiredtherapeutic effect according to the methods of treatment describedherein.

The term “pharmaceutically acceptable carrier” as used herein means acarrier that is conventionally used in the art to facilitate thestorage, administration, and/or the healing effect of a biologicallyactive agent.

The term “intermittent administration” as used herein meansadministration of a therapeutically effective dose of a compositionaccording to the invention, followed by a time period of discontinuance,which is then followed by another administration of a therapeuticallyeffective dose, and so forth.

The term “monoamine” as used herein encompasses monoamineneurotransmitters and neuromodulators. In particular, it is used torefer to dopamine, norepinephrine, and serotonin. Monoamine transportersfacilitate the reuptake or reabsorption of these monoamines into thepresynapses of an individual.

Active Agents

The invention provides bupropion analogue compounds having the followingstructure:

wherein:

R₁-R₅ are each independently selected from H, OH, optionally substitutedC1-4 alkyl, optionally substituted C1-3 alkoxy, optionally substitutedC2-4 alkenyl, optionally substituted C2-4 alkynyl, halogen, amino,acylamido, CN, CF₃, NO₂, N₃, CONH₂, CO₂R₁₂, CH₂OR₁₂, NR₁₂R₁₃, NHCOR₁₂,NHCO₂R₁₂, CONR₁₂R₁₃; C1-3 alkylthio, R₁₂SO, R₁₂SO₂, CF₃S, and CF₃SO₂;

R₆ and R₇ are each independently selected from H or optionallysubstituted C1-10 alkyl, or R₆ and R₇ together constitute ═O or ═CH₂;

R₈ and R₉ are each independently selected from H or optionallysubstituted C1-10 alkyl;

R₁₀, R₁₁, R₁₂, and R₁₃ are each independently selected from H oroptionally substituted C1-10 alkyl;

and wherein R₁ and R₈ may be joined to form a cyclic ring;

or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug,or isomer thereof, with the proviso that when one of R₈ and R₉ is CH₃,then at least one of R₁₀ and R₁₁ is optionally substituted C3-C10cycloalkyl.

Such compounds of the present invention may be capable of affectingmonoamine uptake efficacy. In particular, in some embodiments, compoundsof the present invention may be capable of inhibiting dopamine and/ornorepinephrine reuptake. In preferred embodiments, the compounds may becapable of selectively inhibiting dopamine reuptake.

In preferred embodiments of Formula I, R₁-R₅ are independently H or ahalogen. In some embodiments, R₁ and R₅ are H and R₂-R₄ may be H orhalogen. In some preferred embodiments, one of R₈ and R₉ is H and theother is an optionally substituted C1-C10 alkyl. In additional preferredembodiments, R₆ and R₇ together constitute ═O. In some preferredembodiments, one of R₁₀ and R₁₁ is H and the other of R₁₀ and R₁₁ is anoptionally substituted cycloalkyl. In some additional preferredembodiments, one of R₁₀ and R₁₁ is H and the other of R₁₀ and R₁₁ is anoptionally substituted cyclopropyl. According to one embodiment, atleast one of R₈ or R₉ is a C2-C10 alkyl and/or at least one of R₁₀ andR₁₁ is a C3-C10 cycloalkyl.

In particular embodiments, compounds according to the followingstructure are provided:

wherein:

R₁-R₅ are each independently selected from H, OH, optionally substitutedC1-4 alkyl, optionally substituted C1-3 alkoxy, optionally substitutedC2-4 alkenyl, optionally substituted C2-4 alkynyl, halogen, amino,acylamido, CN, CF₃, NO₂, N₃, CONH₂, CO₂R₁₂, CH₂OR₁₂, NR₁₂R₁₃, NHCOR₁₂,NHCO₂R₁₂, CONR₁₂R₁₃; C1-3 alkylthio, R₁₂SO, R₁₂SO₂, CF₃S, and CF₃SO₂;

R₈ and R₉ are each independently selected from H or optionallysubstituted C1-10 alkyl;

R₁₀, R₁₁, R₁₂, and R₁₃ are each independently selected from H oroptionally substituted C1-10 alkyl;

and wherein R₁ and R₈ may be joined to form a cyclic ring,

or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug,or isomer thereof, with the proviso that when one of R₈ and R₉ is CH₃,then at least one of R₁₀ and R₁₁ is optionally substituted C3-C10cycloalkyl.

In preferred embodiments of Formula Ia, R₁-R₅ are independently H or ahalogen. In some embodiments, R₁ and R₅ are H and R₂-R₄ may be H orhalogen. In some preferred embodiments, one of R₈ and R₉ is H and theother is an optionally substituted C1-C10 alkyl. In additional preferredembodiments, one of R₁₀ and R₁₁ is H and the other of R₁₀ and R₁₁ is anoptionally substituted cycloalkyl. In some additional preferredembodiments, one of R₁₀ and R₁₁ is H and the other of R₁₀ and R₁₁ is anoptionally substituted cyclopropyl.

In further particular embodiments, compounds according to the followingstructure are provided:

wherein:

R₁-R₅ are each independently selected from H, OH, optionally substitutedC1-4 alkyl, optionally substituted C1-3 alkoxy, optionally substitutedC2-4 alkenyl, optionally substituted C2-4 alkynyl, halogen, amino,acylamido, CN, CF₃, NO₂, N₃, CONH₂, CO₂R₁₂, CH₂OR₁₂, NR₁₂R₁₃, NHCOR₁₂,NHCO₂R₁₂, CONR₁₁R₁₃; C1-3 alkylthio, R₁₂SO, R₁₂SO₂, CF₃S, and CF₃SO₂;

R₈ and R₉ are each independently selected from H or optionallysubstituted C1-10 alkyl;

R₁₂ and R₁₃ are each independently selected from H or optionallysubstituted C1-10alkyl;

and wherein R₁ and R₈ may be joined to form a cyclic ring,

or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug,or isomer thereof.

In preferred embodiments of Formula Ib, R₁-R₅ are independently H or ahalogen. In some embodiments, R₁ and R₅ are H and R₂-R₄ may be H orhalogen. In some preferred embodiments, one of R₈ and R₉ is H and theother is an optionally substituted C1-C10 alkyl.

In some embodiments, compounds with one or more chiral centers areprovided. While racemic mixtures of compounds of the invention can beactive, selective, and bioavailable, isolated isomers may be of interestas well.

The compounds disclosed herein as active agents may contain chiralcenters, which may be either of the (R) or (S) configuration, or maycomprise a mixture thereof. Accordingly, the present invention alsoincludes stereoisomers of the compounds described herein, whereapplicable, either individually or admixed in any proportions.Stereoisomers may include, but are not limited to, enantiomers,diastereomers, racemic mixtures, and combinations thereof. Suchstereoisomers can be prepared and separated using conventionaltechniques, either by reacting enantiomeric starting materials, or byseparating isomers of compounds of the present invention. Isomers mayinclude geometric isomers. Examples of geometric isomers include, butare not limited to, cis isomers or trans isomers across a double bond.Other isomers are contemplated among the compounds of the presentinvention. The isomers may be used either in pure form or in admixturewith other isomers of the compounds described herein.

Various methods are known in the art for preparing optically activeforms and determining activity. Such methods include standard testsdescribed herein other similar tests which are will known in the art.Examples of methods that can be used to obtain optical isomers of thecompounds according to the present invention include the following:

i) physical separation of crystals whereby macroscopic crystals of theindividual enantiomers are manually separated. This technique mayparticularly be used when crystals of the separate enantiomers exist(i.e., the material is a conglomerate), and the crystals are visuallydistinct;

ii) simultaneous crystallization whereby the individual enantiomers areseparately crystallized from a solution of the racemate, possible onlyif the latter is a conglomerate in the solid state;

iii) enzymatic resolutions whereby partial or complete separation of aracemate by virtue of differing rates of reaction for the enantiomerswith an enzyme;

iv) enzymatic asymmetric synthesis, a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) chemical asymmetric synthesis whereby the desired enantiomer issynthesized from an achiral precursor under conditions that produceasymmetry (i.e., chirality) in the product, which may be achieved usingchiral catalysts or chiral auxiliaries;

vi) diastereomer separations whereby a racemic compound is reacted withan enantiomerically pure reagent (the chiral auxiliary) that convertsthe individual enantiomers to diastereomers. The resulting diastereomersare then separated by chromatography or crystallization by virtue oftheir now more distinct structural differences and the chiral auxiliarylater removed to obtain the desired enantiomer;

vii) first- and second-order asymmetric transformations wherebydiastereomers from the racemate equilibrate to yield a preponderance insolution of the diastereomer from the desired enantiomer or wherepreferential crystallization of the diastereomer from the desiredenantiomer perturbs the equilibrium such that eventually in principleall the material is converted to the crystalline diastereomer from thedesired enantiomer. The desired enantiomer is then released from thediastereomers;

viii) kinetic resolutions comprising partial or complete resolution of aracemate (or of a further resolution of a partially resolved compound)by virtue of unequal reaction rates of the enantiomers with a chiral,non-racemic reagent or catalyst under kinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors whereby thedesired enantiomer is obtained from non-chiral starting materials andwhere the stereochemical integrity is not or is only minimallycompromised over the course of the synthesis;

x) chiral liquid chromatography whereby the enantiomers of a racemateare separated in a liquid mobile phase by virtue of their differinginteractions with a stationary phase. The stationary phase can be madeof chiral material or the mobile phase can contain an additional chiralmaterial to provoke the differing interactions;

xi) chiral gas chromatography whereby the racemate is volatilized andenantiomers are separated by virtue of their differing interactions inthe gaseous mobile phase with a column containing a fixed non-racemicchiral adsorbent phase;

xii) extraction with chiral solvents whereby the enantiomers areseparated by virtue of preferential dissolution of one enantiomer into aparticular chiral solvent; and

xiii) transport across chiral membranes whereby a racemate is placed incontact with a thin membrane barrier. The barrier typically separatestwo miscible fluids, one containing the racemate, and a driving forcesuch as concentration or pressure differential causes preferentialtransport across the membrane barrier. Separation occurs as a result ofthe non-racemic chiral nature of the membrane which allows only oneenantiomer of the racemate to pass through.

The compound optionally may be provided in a composition that isenantiomerically enriched, such as a mixture of enantiomers in which oneenantiomer is present in excess, in particular to the extent of 95% ormore, or 98% or more, including 100%.

In some embodiments, a compound according to Formula I is provided,wherein R₆ and R₇ are not the same substituent, forming a chiral centerat the carbon to which R₆ and R₇ are attached. The compound may be the Ror S enantiomer. In some embodiments, a compound according to Formula Iis provided, wherein R₈ and R₉ are not the same substituent, forming achiral center at the carbon to which R₈ and R₉ are attached. Thecompound may be the R or S enantiomer. In some embodiments, R₆ and R₇are not the same substituent, forming a chiral center at the carbon towhich R₆ and R₇ are attached and R₈ and R₉ are not the same substituent,forming a chiral center at the carbon to which R₈ and R₉ are attached.These compounds may be (R,R), (S,S), (R,S), or (S,R) isomers.

The terms (R), (S), (R,R), (S,S), (R,S) and (S,R) as used herein meanthat the composition contains a greater proportion of the named isomerof the compound in relation to other isomers. In a preferred embodiment,these terms indicate that the composition contains at least 90% byweight of the named isomer and 10% by weight or less of the one or moreother isomers; or more preferably about 95% by weight of the namedisomer and 5% or less of the one or more other isomers. Thesepercentages are based on the total amount of the compound of the presentinvention present in the composition.

The compounds of the present invention may be utilized per se or in theform of a pharmaceutically acceptable ester, amide, salt, solvate,prodrug, or isomer. For example, the compound may be provided as apharmaceutically acceptable salt. If used, a salt of the drug compoundshould be both pharmacologically and pharmaceutically acceptable, butnon-pharmaceutically acceptable salts may conveniently be used toprepare the free active compound or pharmaceutically acceptable saltsthereof and are not excluded from the scope of this invention. Suchpharmacologically and pharmaceutically acceptable salts can be preparedby reaction of the drug with an organic or inorganic acid, usingstandard methods detailed in the literature. Examples ofpharmaceutically acceptable salts of the compounds useful according tothe invention include acid addition salts. Salts of non-pharmaceuticallyacceptable acids, however, may be useful, for example, in thepreparation and purification of the compounds. Suitable acid additionsalts according to the present invention include organic and inorganicacids. Preferred salts include those formed from hydrochloric,hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic,acetic, succinic, fumaric, maleic, oxaloacetic, methanesulfonic,ethanesulfonic, p-toluenesulfonic, benzenesulfonic, and isethionicacids. Other useful acid addition salts include propionic acid, glycolicacid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamicacid, mandelic acid, salicylic acid, and the like. Particular example ofpharmaceutically acceptable salts include, but are not limited to,sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxyenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methanesulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

An acid addition salt may be reconverted to the free base by treatmentwith a suitable base. Preparation of basic salts of acid moieties whichmay be present on a compound useful according to the present inventionmay be prepared in a similar manner using a pharmaceutically acceptablebase, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,calcium hydroxide, triethylamine, or the like.

Esters of the active agent compounds according to the present inventionmay be prepared through functionalization of hydroxyl and/or carboxylgroups that may be present within the molecular structure of thecompound. Amides and prodrugs may also be prepared using techniquesknown to those skilled in the art. For example, amides may be preparedfrom esters, using suitable amine reactants, or they may be preparedfrom anhydride or an acid chloride by reaction with ammonia or a loweralkyl amine. Moreover, esters and amides of compounds of the inventioncan be made by reaction with a carbonylating agent (e.g., ethyl formate,acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methylisocyanate, ethyl chloroformate, methanesulfonyl chloride) and asuitable base (e.g., 4-dimethylaminopyridine, pyridine, triethylamine,potassium carbonate) in a suitable organic solvent (e.g.,tetrahydrofuran, acetone, methanol, pyridine, N,N-dimethylformamide) ata temperature of 0° C. to 60° C. Prodrugs are typically prepared bycovalent attachment of a moiety, which results in a compound that istherapeutically inactive until modified by an individual's metabolicsystem. Examples of pharmaceutically acceptable solvates include, butare not limited to, compounds according to the invention in combinationwith water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, aceticacid, or ethanolamine.

In the case of solid compositions, it is understood that the compoundsused in the methods of the invention may exist in different forms. Forexample, the compounds may exist in stable and metastable crystallineforms and isotropic and amorphous forms, all of which are intended to bewithin the scope of the present invention.

If a compound useful as an active agent according to the invention is abase, the desired salt may be prepared by any suitable method known tothe art, including treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,pyranosidyl acids such as glucuronic acid and galacturonic acid,alpha-hydroxy acids such as citric acid and tartaric acid, amino acidssuch as aspartic acid and glutamic acid, aromatic acids such as benzoicacid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid orethanesulfonic acid, or the like.

If a compound described herein as an active agent is an acid, thedesired salt may be prepared by any suitable method known to the art,including treatment of the free acid with an inorganic or organic base,such as an amine (primary, secondary or tertiary), an alkali metal oralkaline earth metal hydroxide or the like. Illustrative examples ofsuitable salts include organic salts derived from amino acids such asglycine and arginine, ammonia, primary, secondary and tertiary amines,and cyclic amines such as piperidine, morpholine and piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum and lithium.

The present invention further includes prodrugs and active metabolitesof the active agent compounds described herein. Any of the compoundsdescribed herein can be administered as a prodrug to increase theactivity, bioavailability, or stability of the compound or to otherwisealter the properties of the compound. Typical examples of prodrugsinclude compounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, and/or dephosphorylated to producethe active compound.

A number of prodrug ligands are known. In general, alkylation,acylation, or other lipophilic modification of one or more heteroatomsof the compound, such as a free amine or carboxylic acid residue,reduces polarity and allows passage into cells. Examples of substituentgroups that can replace one or more hydrogen atoms on the free amineand/or carboxylic acid moiety include, but are not limited to, thefollowing: aryl; steroids; carbohydrates (including sugars);1,2-diacylglycerol; alcohols; acyl (including lower acyl); alkyl(including lower alkyl); sulfonate ester (including alkyl or arylalkylsulfonyl, such as methanesulfonyl and benzyl, wherein the phenyl groupis optionally substituted with one or more substituents as provided inthe definition of an aryl given herein); optionally substitutedarylsulfonyl; lipids (including phospholipids); phosphotidylcholine;phosphocholine; amino acid residues or derivatives; amino acid acylresidues or derivatives; peptides; cholesterols; or otherpharmaceutically acceptable leaving groups which, when administered invivo, provide the free amine and/or carboxylic acid moiety. Any of thesecan be used in combination with the disclosed active agents to achieve adesired effect.

In particular embodiments, the present invention provides a compoundwherein R₆ and R₇ together constitute ═O. In particular embodiments, thepresent invention provides a compound wherein R₈ and R₉ areindependently selected from H and optionally substituted C1-10 alkyl. Insome embodiments, R₈ and R₉ are independently selected from H andoptionally substituted C1-7 alkyl, preferably C1-6 alkyl. In someembodiments, R₈ and R₉ are independently selected from H and optionallysubstituted C2-7 alkyl, preferably C2-6 alkyl. In some embodiments, oneof R₈ and R₉ is H and the other of R₈ and R₉ is optionally substitutedC1-10 alkyl. In some embodiments, one of R₈ and R₉ is H and the other ofR₈ and R₉ is optionally substituted C1-7 alkyl, and preferably, isoptionally substituted C1-6 alkyl. In some embodiments, one of R₈ and R₉is H and the other of R₈ and R₉ is optionally substituted C2-7 alkyl,and preferably, is optionally substituted C2-6 alkyl. In someembodiments, the C2-C7 alkyl is selected from the group consisting ofethyl, propyl, butyl, hexyl, or isobutyl. In some embodiments, one of R₈and R₉ is H and the other of R₈ and R₉ is optionally substituted C1-4alkyl, preferably C2-4 alkyl. In certain embodiments, one of R₁₀ and R₁₁is H and the other of R₁₀ and R₁₁ is optionally substituted C1-10 alkyl.In some embodiments, one of R₁₀ and R₁₁ is H and the other of R₁₀ andR₁₁ is tert-butyl. In some embodiments, one of R₁₀ and R₁₁ is H and theother of R₁₀ and R₁₁ is optionally substituted C3-10 cycloalkyl. In someembodiments, the cycloalkyl is selected from the group consisting ofcyclopropyl, cyclobutyl, and cyclopentyl. In particular embodiments, thepresent invention provides a compound wherein one or more of R₁-R₅ is asubstituent other than H. For example, in some embodiments, one or moreof R₁-R₅ is a halogen (e.g., Cl, Br, or I).

Particularly preferred compounds of the present invention include thefollowing:

Additional representative, non-limiting compounds of Formula I of thepresent invention are indicated below in Table 1, wherein R₁₁ is acycloalkyl.

TABLE 1 Formula I

Representative compounds of Formula I R₁ R₂ R₃ R₄ R₅ R₆ R₇ R₈ R₉ R₁₀ R₁₁H H H H H CH₃ H CH₃ H H CH(CH₂CH₂) H Cl H H H CH₃ H CH₃ H H CH(CH₂CH₂) HH Cl H H CH₃ H CH₃ H H CH(CH₂CH₂) H H H Cl H CH₃ H CH₃ H H CH(CH₂CH₂) HBr H H H CH₃ H CH₃ H H CH(CH₂CH₂) H H Br H H CH₃ H CH₃ H H CH(CH₂CH₂) HH H Br H CH₃ H CH₃ H H CH(CH₂CH₂) H CH₃ H H H CH₃ H CH₃ H H CH(CH₂CH₂) HH CH₃ H H CH₃ H CH₃ H H CH(CH₂CH₂) H H H CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂)H F H H H CH₃ H CH₃ H H CH(CH₂CH₂) H H F H H CH₃ H CH₃ H H CH(CH₂CH₂) HH H F H CH₃ H CH₃ H H CH(CH₂CH₂) H Cl Cl H H CH₃ H CH₃ H H CH(CH₂CH₂) HBr Br H H CH₃ H CH₃ H H CH(CH₂CH₂) H F F H H CH₃ H CH₃ H H CH(CH₂CH₂) HCH₃ CH₃ H H CH₃ H CH₃ H H CH(CH₂CH₂) H Cl CH₃ H H CH₃ H CH₃ H HCH(CH₂CH₂) H Br CH₃ H H CH₃ H CH₃ H H CH(CH₂CH₂) H F CH₃ H H CH₃ H CH₃ HH CH(CH₂CH₂) H CH₃ Cl H H CH₃ H CH₃ H H CH(CH₂CH₂) H CH₃ Br H H CH₃ HCH₃ H H CH(CH₂CH₂) H CH₃ F H H CH₃ H CH₃ H H CH(CH₂CH₂) H Cl H Cl H CH₃H CH₃ H H CH(CH₂CH₂) H Br H Br H CH₃ H CH₃ H H CH(CH₂CH₂) H F H F H CH₃H CH₃ H H CH(CH₂CH₂) H CH₃ H CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂) H Cl H Cl HCH₃ H CH₃ H H CH(CH₂CH₂) H Br H Br H CH₃ H CH₃ H H CH(CH₂CH₂) H F H F HCH₃ H CH₃ H H CH(CH₂CH₂) H H CH₃ CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂) H H ClCl H CH₃ H CH₃ H H CH(CH₂CH₂) H H Br Br H CH₃ H CH₃ H H CH(CH₂CH₂) H H FF H CH₃ H CH₃ H H CH(CH₂CH₂) H H Cl CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂) H HBr CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂) H H F CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂) HH CH₃ Cl H CH₃ H CH₃ H H CH(CH₂CH₂) H H CH₃ Br H CH₃ H CH₃ H HCH(CH₂CH₂) H H CH₃ F H CH₃ H CH₃ H H CH(CH₂CH₂) H H H H H CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H Cl H H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Cl H H CH₃ HCH₃ H H CH(CH₂CH₂CH₂) H H H Cl H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Br H H HCH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Br H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H HBr H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H CH₃ H H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂)H H CH₃ H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H H CH₃ H CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H F H H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H F H H CH₃ H CH₃H H CH(CH₂CH₂CH₂) H H H F H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Cl Cl H H CH₃H CH₃ H H CH(CH₂CH₂CH₂) H Br Br H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F F HH CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H CH₃ CH₃ H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂)H Cl CH₃ H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Br CH₃ H H CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H F CH₃ H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H CH₃ Cl H H CH₃ HCH₃ H H CH(CH₂CH₂CH₂) H CH₃ Br H H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H CH₃ F HH CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Cl H Cl H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) HBr H Br H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F H F H CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H CH₃ H CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Cl H Cl H CH₃H CH₃ H H CH(CH₂CH₂CH₂) H Br H Br H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F H FH CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H CH₃ CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂CH₂)H H Cl Cl H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Br Br H CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H H F F H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Cl CH₃ H CH₃ HCH₃ H H CH(CH₂CH₂CH₂) H H Br CH₃ H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H F CH₃H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H CH₃ Cl H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) HH CH₃ Br H CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H CH₃ F H CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H H H H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H Cl H H H CH₂CH₃ HCH₃ H H CH(CH₂CH₂) H H Cl H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H H Cl HCH₂CH₃ H CH₃ H H CH(CH₂CH₂) H Br H H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H HBr H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H H Br H CH₂CH₃ H CH₃ H HCH(CH₂CH₂) H CH₃ H H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H CH₃ H H CH₂CH₃ HCH₃ H H CH(CH₂CH₂) H H H CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H F H H HCH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H F H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H HF H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H Cl Cl H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂)H Br Br H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H F F H H CH₂CH₃ H CH₃ H HCH(CH₂CH₂) H CH₃ CH₃ H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H Cl CH₃ H H CH₂CH₃H CH₃ H H CH(CH₂CH₂) H Br CH₃ H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H F CH₃ HH CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H CH₃ Cl H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) HCH₃ Br H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H CH₃ F H H CH₂CH₃ H CH₃ H HCH(CH₂CH₂) H Cl H Cl H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H Br H Br H CH₂CH₃ HCH₃ H H CH(CH₂CH₂) H F H F H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H CH₃ H CH₃ HCH₂CH₃ H CH₃ H H CH(CH₂CH₂) H Cl H Cl H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H BrH Br H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H F H F H CH₂CH₃ H CH₃ H H CH(CH₂CH₂)H H CH₃ CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H Cl Cl H CH₂CH₃ H CH₃ H HCH(CH₂CH₂) H H Br Br H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H F F H CH₂CH₃ HCH₃ H H CH(CH₂CH₂) H H Cl CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H Br CH₃ HCH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H F CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H HCH₃ Cl H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H CH₃ Br H CH₂CH₃ H CH₃ H HCH(CH₂CH₂) H H CH₃ F H CH₂CH₃ H CH₃ H H CH(CH₂CH₂) H H H H H CH₂CH₃ HCH₃ H H CH(CH₂CH₂CH₂) H Cl H H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Cl HH CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H H Cl H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H Br H H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Br H HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H H Br H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂)H CH₃ H H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H CH₃ H H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H H H CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F H H HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H F H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂)H H H F H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Cl Cl H H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H Br Br H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F F H HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H CH₃ CH₃ H H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H Cl CH₃ H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Br CH₃ H HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F CH₃ H H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H CH₃ Cl H H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H CH₃ Br H HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H CH₃ F H H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H Cl H Cl H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Br H Br HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F H F H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂)H CH₃ H CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H Cl H Cl H CH₂CH₃ H CH₃ HH CH(CH₂CH₂CH₂) H Br H Br H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H F H F HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H CH₃ CH₃ H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H H Cl Cl H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Br Br HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H F F H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂)H H Cl CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H Br CH₃ H CH₂CH₃ H CH₃ HH CH(CH₂CH₂CH₂) H H F CH₃ H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H CH₃ Cl HCH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂) H H CH₃ Br H CH₂CH₃ H CH₃ H HCH(CH₂CH₂CH₂) H H CH₃ F H CH₂CH₃ H CH₃ H H CH(CH₂CH₂CH₂)

Additional representative, non-limiting compounds of the presentinvention encompassed by Formula Ia are indicated below in Table 2,wherein R₈ is ethyl or propyl.

TABLE 2 Formula Ia

Representative compounds of Formula Ia R₁ R₂ R₃ R₄ R₅ R₈ R₉ R₁₀ R₁₁ H HH H H C₂H₅ H H C(CH₃)₃ H Cl H H H C₂H₅ H H C(CH₃)₃ H H Cl H H C₂H₅ H HC(CH₃)₃ H H H Cl H C₂H₅ H H C(CH₃)₃ H Br H H H C₂H₅ H H C(CH₃)₃ H H Br HH C₂H₅ H H C(CH₃)₃ H H H Br H C₂H₅ H H C(CH₃)₃ H CH₃ H H H C₂H₅ H HC(CH₃)₃ H H CH₃ H H C₂H₅ H H C(CH₃)₃ H H H CH₃ H C₂H₅ H H C(CH₃)₃ H F HH H C₂H₅ H H C(CH₃)₃ H H F H H C₂H₅ H H C(CH₃)₃ H H H F H C₂H₅ H HC(CH₃)₃ H Cl Cl H H C₂H₅ H H C(CH₃)₃ H Br Br H H C₂H₅ H H C(CH₃)₃ H F FH H C₂H₅ H H C(CH₃)₃ H CH₃ CH₃ H H C₂H₅ H H C(CH₃)₃ H Cl CH₃ H H C₂H₅ HH C(CH₃)₃ H Br CH₃ H H C₂H₅ H H C(CH₃)₃ H F CH₃ H H C₂H₅ H H C(CH₃)₃ HCH₃ Cl H H C₂H₅ H H C(CH₃)₃ H CH₃ Br H H C₂H₅ H H C(CH₃)₃ H CH₃ F H HC₂H₅ H H C(CH₃)₃ H Cl H Cl H C₂H₅ H H C(CH₃)₃ H Br H Br H C₂H₅ H HC(CH₃)₃ H F H F H C₂H₅ H H C(CH₃)₃ H CH₃ H CH₃ H C₂H₅ H H C(CH₃)₃ H Cl HCl H C₂H₅ H H C(CH₃)₃ H Br H Br H C₂H₅ H H C(CH₃)₃ H F H F H C₂H₅ H HC(CH₃)₃ H H CH₃ CH₃ H C₂H₅ H H C(CH₃)₃ H H Cl Cl H C₂H₅ H H C(CH₃)₃ H HBr Br H C₂H₅ H H C(CH₃)₃ H H F F H C₂H₅ H H C(CH₃)₃ H H Cl CH₃ H C₂H₅ HH C(CH₃)₃ H H Br CH₃ H C₂H₅ H H C(CH₃)₃ H H F CH₃ H C₂H₅ H H C(CH₃)₃ H HCH₃ Cl H C₂H₅ H H C(CH₃)₃ H H CH₃ Br H C₂H₅ H H C(CH₃)₃ H H CH₃ F H C₂H₅H H C(CH₃)₃ H H H H H C₃H₇ H H C(CH₃)₃ H Cl H H H C₃H₇ H H C(CH₃)₃ H HCl H H C₃H₇ H H C(CH₃)₃ H H H Cl H C₃H₇ H H C(CH₃)₃ H Br H H H C₃H₇ H HC(CH₃)₃ H H Br H H C₃H₇ H H C(CH₃)₃ H H H Br H C₃H₇ H H C(CH₃)₃ H CH₃ HH H C₃H₇ H H C(CH₃)₃ H H CH₃ H H C₃H₇ H H C(CH₃)₃ H H H CH₃ H C₃H₇ H HC(CH₃)₃ H F H H H C₃H₇ H H C(CH₃)₃ H H F H H C₃H₇ H H C(CH₃)₃ H H H F HC₃H₇ H H C(CH₃)₃ H Cl Cl H H C₃H₇ H H C(CH₃)₃ H Br Br H H C₃H₇ H HC(CH₃)₃ H F F H H C₃H₇ H H C(CH₃)₃ H CH₃ CH₃ H H C₃H₇ H H C(CH₃)₃ H ClCH₃ H H C₃H₇ H H C(CH₃)₃ H Br CH₃ H H C₃H₇ H H C(CH₃)₃ H F CH₃ H H C₃H₇H H C(CH₃)₃ H CH₃ Cl H H C₃H₇ H H C(CH₃)₃ H CH₃ Br H H C₃H₇ H H C(CH₃)₃H CH₃ F H H C₃H₇ H H C(CH₃)₃ H Cl H Cl H C₃H₇ H H C(CH₃)₃ H Br H Br HC₃H₇ H H C(CH₃)₃ H F H F H C₃H₇ H H C(CH₃)₃ H CH₃ H CH₃ H C₃H₇ H HC(CH₃)₃ H Cl H Cl H C₃H₇ H H C(CH₃)₃ H Br H Br H C₃H₇ H H C(CH₃)₃ H F HF H C₃H₇ H H C(CH₃)₃ H H CH₃ CH₃ H C₃H₇ H H C(CH₃)₃ H H Cl Cl H C₃H₇ H HC(CH₃)₃ H H Br Br H C₃H₇ H H C(CH₃)₃ H H F F H C₃H₇ H H C(CH₃)₃ H H ClCH₃ H C₃H₇ H H C(CH₃)₃ H H Br CH₃ H C₃H₇ H H C(CH₃)₃ H H F CH₃ H C₃H₇ HH C(CH₃)₃ H H CH₃ Cl H C₃H₇ H H C(CH₃)₃ H H CH₃ Br H C₃H₇ H H C(CH₃)₃ HH CH₃ F H C₃H₇ H H C(CH₃)₃ H H H H H C₂H₅ H H CH(CH₂CH₂CH₂) H Cl H H HC₂H₅ H H CH(CH₂CH₂CH₂) H H Cl H H C₂H₅ H H CH(CH₂CH₂CH₂) H H H Cl H C₂H₅H H CH(CH₂CH₂CH₂) H Br H H H C₂H₅ H H CH(CH₂CH₂CH₂) H H Br H H C₂H₅ H HCH(CH₂CH₂CH₂) H H H Br H C₂H₅ H H CH(CH₂CH₂CH₂) H CH₃ H H H C₂H₅ H HCH(CH₂CH₂CH₂) H H CH₃ H H C₂H₅ H H CH(CH₂CH₂CH₂) H H H CH₃ H C₂H₅ H HCH(CH₂CH₂CH₂) H F H H H C₂H₅ H H CH(CH₂CH₂CH₂) H H F H H C₂H₅ H HCH(CH₂CH₂CH₂) H H H F H C₂H₅ H H CH(CH₂CH₂CH₂) H Cl Cl H H C₂H₅ H HCH(CH₂CH₂CH₂) H Br Br H H C₂H₅ H H CH(CH₂CH₂CH₂) H F F H H C₂H₅ H HCH(CH₂CH₂CH₂) H CH₃ CH₃ H H C₂H₅ H H CH(CH₂CH₂CH₂) H Cl CH₃ H H C₂H₅ H HCH(CH₂CH₂CH₂) H Br CH₃ H H C₂H₅ H H CH(CH₂CH₂CH₂) H F CH₃ H H C₂H₅ H HCH(CH₂CH₂CH₂) H CH₃ Cl H H C₂H₅ H H CH(CH₂CH₂CH₂) H CH₃ Br H H C₂H₅ H HCH(CH₂CH₂CH₂) H CH₃ F H H C₂H₅ H H CH(CH₂CH₂CH₂) H Cl H Cl H C₂H₅ H HCH(CH₂CH₂CH₂) H Br H Br H C₂H₅ H H CH(CH₂CH₂CH₂) H F H F H C₂H₅ H HCH(CH₂CH₂CH₂) H CH₃ H CH₃ H C₂H₅ H H CH(CH₂CH₂CH₂) H Cl H Cl H C₂H₅ H HCH(CH₂CH₂CH₂) H Br H Br H C₂H₅ H H CH(CH₂CH₂CH₂) H F H F H C₂H₅ H HCH(CH₂CH₂CH₂) H H CH₃ CH₃ H C₂H₅ H H CH(CH₂CH₂CH₂) H H Cl Cl H C₂H₅ H HCH(CH₂CH₂CH₂) H H Br Br H C₂H₅ H H CH(CH₂CH₂CH₂) H H F F H C₂H₅ H HCH(CH₂CH₂CH₂) H H Cl CH₃ H C₂H₅ H H CH(CH₂CH₂CH₂) H H Br CH₃ H C₂H₅ H HCH(CH₂CH₂CH₂) H H F CH₃ H C₂H₅ H H CH(CH₂CH₂CH₂) H H CH₃ Cl H C₂H₅ H HCH(CH₂CH₂CH₂) H H CH₃ Br H C₂H₅ H H CH(CH₂CH₂CH₂) H H CH₃ F H C₂H₅ H HCH(CH₂CH₂CH₂) H H H H H C₃H₇ H H CH(CH₂CH₂CH₂) H Cl H H H C₃H₇ H HCH(CH₂CH₂CH₂) H H Cl H H C₃H₇ H H CH(CH₂CH₂CH₂) H H H Cl H C₃H₇ H HCH(CH₂CH₂CH₂) H Br H H H C₃H₇ H H CH(CH₂CH₂CH₂) H H Br H H C₃H₇ H HCH(CH₂CH₂CH₂) H H H Br H C₃H₇ H H CH(CH₂CH₂CH₂) H CH₃ H H H C₃H₇ H HCH(CH₂CH₂CH₂) H H CH₃ H H C₃H₇ H H CH(CH₂CH₂CH₂) H H H CH₃ H C₃H₇ H HCH(CH₂CH₂CH₂) H F H H H C₃H₇ H H CH(CH₂CH₂CH₂) H H F H H C₃H₇ H HCH(CH₂CH₂CH₂) H H H F H C₃H₇ H H CH(CH₂CH₂CH₂) H Cl Cl H H C₃H₇ H HCH(CH₂CH₂CH₂) H Br Br H H C₃H₇ H H CH(CH₂CH₂CH₂) H F F H H C₃H₇ H HCH(CH₂CH₂CH₂) H CH₃ CH₃ H H C₃H₇ H H CH(CH₂CH₂CH₂) H Cl CH₃ H H C₃H₇ H HCH(CH₂CH₂CH₂) H Br CH₃ H H C₃H₇ H H CH(CH₂CH₂CH₂) H F CH₃ H H C₃H₇ H HCH(CH₂CH₂CH₂) H CH₃ Cl H H C₃H₇ H H CH(CH₂CH₂CH₂) H CH₃ Br H H C₃H₇ H HCH(CH₂CH₂CH₂) H CH₃ F H H C₃H₇ H H CH(CH₂CH₂CH₂) H Cl H Cl H C₃H₇ H HCH(CH₂CH₂CH₂) H Br H Br H C₃H₇ H H CH(CH₂CH₂CH₂) H F H F H C₃H₇ H HCH(CH₂CH₂CH₂) H CH₃ H CH₃ H C₃H₇ H H CH(CH₂CH₂CH₂) H Cl H Cl H C₃H₇ H HCH(CH₂CH₂CH₂) H Br H Br H C₃H₇ H H CH(CH₂CH₂CH₂) H F H F H C₃H₇ H HCH(CH₂CH₂CH₂) H H CH₃ CH₃ H C₃H₇ H H CH(CH₂CH₂CH₂) H H Cl Cl H C₃H₇ H HCH(CH₂CH₂CH₂) H H Br Br H C₃H₇ H H CH(CH₂CH₂CH₂) H H F F H C₃H₇ H HCH(CH₂CH₂CH₂) H H Cl CH₃ H C₃H₇ H H CH(CH₂CH₂CH₂) H H Br CH₃ H C₃H₇ H HCH(CH₂CH₂CH₂) H H F CH₃ H C₃H₇ H H CH(CH₂CH₂CH₂) H H CH₃ Cl H C₃H₇ H HCH(CH₂CH₂CH₂) H H CH₃ Br H C₃H₇ H H CH(CH₂CH₂CH₂) H H CH₃ F H C₃H₇ H HCH(CH₂CH₂CH₂)

Representative, non-limiting compounds of Formula Ib of the presentinvention are indicated below in Table 3.

TABLE 3 Formula Ib

Representative compounds of Formula Ib R₁ R₂ R₃ R₄ R₅ R₈ R₉ H H H H HCH₃ H H Cl H H H CH₃ H H H Cl H H CH₃ H H H H Cl H CH₃ H H Br H H H CH₃H H H Br H H CH₃ H H H H Br H CH₃ H H CH₃ H H H CH₃ H H H CH₃ H H CH₃ HH H H CH₃ H CH₃ H H F H H H CH₃ H H H F H H CH₃ H H H H F H CH₃ H H ClCl H H CH₃ H H Br Br H H CH₃ H H F F H H CH₃ H H CH₃ CH₃ H H CH₃ H H ClCH₃ H H CH₃ H H Br CH₃ H H CH₃ H H F CH₃ H H CH₃ H H CH₃ Cl H H CH₃ H HCH₃ Br H H CH₃ H H CH₃ F H H CH₃ H H Cl H Cl H CH₃ H H Br H Br H CH₃ H HF H F H CH₃ H H CH₃ H CH₃ H CH₃ H H Cl H Cl H CH₃ H H Br H Br H CH₃ H HF H F H CH₃ H H H CH₃ CH₃ H CH₃ H H H Cl Cl H CH₃ H H H Br Br H CH₃ H HH F F H CH₃ H H H Cl CH₃ H CH₃ H H H Br CH₃ H CH₃ H H H F CH₃ H CH₃ H HH CH₃ Cl H CH₃ H H H CH₃ Br H CH₃ H H H CH₃ F H CH₃ H H H H H H C₂H₅ H HCl H H H C₂H₅ H H H Cl H H C₂H₅ H H H H Cl H C₂H₅ H H Br H H H C₂H₅ H HH Br H H C₂H₅ H H H H Br H C₂H₅ H H CH₃ H H H C₂H₅ H H H CH₃ H H C₂H₅ HH H H CH₃ H C₂H₅ H H F H H H C₂H₅ H H H F H H C₂H₅ H H H H F H C₂H₅ H HCl Cl H H C₂H₅ H H Br Br H H C₂H₅ H H F F H H C₂H₅ H H CH₃ CH₃ H H C₂H₅H H Cl CH₃ H H C₂H₅ H H Br CH₃ H H C₂H₅ H H F CH₃ H H C₂H₅ H H CH₃ Cl HH C₂H₅ H H CH₃ Br H H C₂H₅ H H CH₃ F H H C₂H₅ H H Cl H Cl H C₂H₅ H H BrH Br H C₂H₅ H H F H F H C₂H₅ H H CH₃ H CH₃ H C₂H₅ H H Cl H Cl H C₂H₅ H HBr H Br H C₂H₅ H H F H F H C₂H₅ H H H CH₃ CH₃ H C₂H₅ H H H Cl Cl H C₂H₅H H H Br Br H C₂H₅ H H H F F H C₂H₅ H H H Cl CH₃ H C₂H₅ H H H Br CH₃ HC₂H₅ H H H F CH₃ H C₂H₅ H H H CH₃ Cl H C₂H₅ H H H CH₃ Br H C₂H₅ H H HCH₃ F H C₂H₅ H H H H H H C₃H₇ H H Cl H H H C₃H₇ H H H Cl H H C₃H₇ H H HH Cl H C₃H₇ H H Br H H H C₃H₇ H H H Br H H C₃H₇ H H H H Br H C₃H₇ H HCH₃ H H H C₃H₇ H H H CH₃ H H C₃H₇ H H H H CH₃ H C₃H₇ H H F H H H C₃H₇ HH H F H H C₃H₇ H H H H F H C₃H₇ H H Cl Cl H H C₃H₇ H H Br Br H H C₃H₇ HH F F H H C₃H₇ H H CH₃ CH₃ H H C₃H₇ H H Cl CH₃ H H C₃H₇ H H Br CH₃ H HC₃H₇ H H F CH₃ H H C₃H₇ H H CH₃ Cl H H C₃H₇ H H CH₃ Br H H C₃H₇ H H CH₃F H H C₃H₇ H H Cl H Cl H C₃H₇ H H Br H Br H C₃H₇ H H F H F H C₃H₇ H HCH₃ H CH₃ H C₃H₇ H H Cl H Cl H C₃H₇ H H Br H Br H C₃H₇ H H F H F H C₃H₇H H H CH₃ CH₃ H C₃H₇ H H H Cl Cl H C₃H₇ H H H Br Br H C₃H₇ H H H F F HC₃H₇ H H H Cl CH₃ H C₃H₇ H H H Br CH₃ H C₃H₇ H H H F CH₃ H C₃H₇ H H HCH₃ Cl H C₃H₇ H H H CH₃ Br H C₃H₇ H H H CH₃ F H C₃H₇ H

In particular embodiments, the compounds of the present invention arecompounds of Formula Ia, which include one or more of the following: analkyl group alpha to the ketone, one or more substituents on the phenylring, and/or one or more alkyl substituents on the amine. Such compoundsmay show enhanced activity in monoamine transporter binding propertiesand may effectively inhibit monoamine uptake.

Methods of Preparation

The present invention also encompasses methods of preparing compoundswith structures encompassed by Formula I, Formula Ia, and/or Formula Ib.Scheme 1 shows a general synthesis used for some compounds representedby Formula Ia of the present invention. In general, the originalprocedure used to prepare bupropion and modified by Chenard andco-workers was followed. See Mehta, N. B., The Chemistry of Bupropion,J. Clin. Psychiat. 1983, 45, (5 (sec. 2)), 56-59 and Chenard, B L. etal.,(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol:A Potent New Neuroprotectant Which Blocks N-methyl-D-aspartateResponses, J. Med. Chem. 1995, 38, 3138-3145, both of which areincorporated by reference herein. Briefly, a benzonitrile is convertedto a substituted phenone, which is brominated at the carbon alpha to thecarbonyl to form a bromo intermediate, which can then be reacted with anamine by nucleophilic substitution to form the amine. One of skill inthe art would be able to adapt this method as required to accommodatevarious functional groups that may affect the chemistry of thesynthesis.

Compositions

While it is possible for the compounds of the present invention to beadministered in the raw chemical form, it is preferred for the compoundsto be delivered as a pharmaceutical formulation. Accordingly, there areprovided by the present invention pharmaceutical compositions comprisingat least one compound capable of inhibiting the reuptake of one or moremonoamines. As such, the formulations of the present invention comprisea compound of Formula I, as described above, or a pharmaceuticallyacceptable ester, amide, salt, or solvate thereof, together with one ormore pharmaceutically acceptable carriers therefore, and optionally,other therapeutic ingredients.

By “pharmaceutically acceptable carrier” is intended a carrier that isconventionally used in the art to facilitate the storage,administration, and/or the healing effect of the agent. The carrier(s)must be pharmaceutically acceptable in the sense of being compatiblewith the other ingredients of the formulation and not unduly deleteriousto the recipient thereof. A carrier may also reduce any undesirable sideeffects of the agent. Such carriers are known in the art. See, Wang etal. (1980) J. Parent Drug Assn. 34(6):452-462, herein incorporated byreference in its entirety.

Adjuvants or accessory ingredients for use in the formulations of thepresent invention can include any pharmaceutical ingredient commonlydeemed acceptable in the art, such as binders, fillers, lubricants,disintegrants, diluents, surfactants, stabilizers, preservatives,flavoring and coloring agents, and the like. The compositions mayfurther include diluents, buffers, binders, disintegrants, thickeners,lubricants, preservatives (including antioxidants), flavoring agents,taste-masking agents, inorganic salts (e.g., sodium chloride),antimicrobial agents (e.g., benzalkonium chloride), sweeteners,antistatic agents, surfactants (e.g., polysorbates such as “TWEEN 20”and “TWEEN 80”, and pluronics such as F68 and F88, available from BASF),sorbitan esters, lipids (e.g., phospholipids such as lecithin and otherphosphatidylcholines, phosphatidylethanolamines, fatty acids and fattyesters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA,zinc and other such suitable cations). Other pharmaceutical excipientsand/or additives suitable for use in the compositions according to theinvention are listed in “Remington: The Science & Practice of Pharmacy,”19^(th) ed., Williams & Williams, (1995), in the “Physician's DeskReference,” 52^(nd) ed., Medical Economics, Montvale, N.J. (1998), andin “Handbook of Pharmaceutical Excipients,” Third Ed., Ed. A. H. Kibbe,Pharmaceutical Press, 2000.

Binders are generally used to facilitate cohesiveness of the tablet andensure the tablet remains intact after compression. Suitable bindersinclude, but are not limited to: starch, polysaccharides, gelatin,polyethylene glycol, propylene glycol, waxes, and natural and syntheticgums. Acceptable fillers include silicon dioxide, titanium dioxide,alumina, talc, kaolin, powdered cellulose, and microcrystallinecellulose, as well as soluble materials, such as mannitol, urea,sucrose, lactose, dextrose, sodium chloride, and sorbitol. Lubricantsare useful for facilitating tablet manufacture and include vegetableoils, glycerin, magnesium stearate, calcium stearate, and stearic acid.Disintegrants, which are useful for facilitating disintegration of thetablet, generally include starches, clays, celluoses, algins, gums, andcrosslinked polymers. Diluents, which are generally included to providebulk to the tablet, may include dicalcium phosphate, calcium sulfate,lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, andpowdered sugar. Surfactants suitable for use in the formulationaccording to the present invention may be anionic, cationic, amphoteric,or nonionic surface active agents. Stabilizers may be included in theformulations to inhibit or lessen reactions leading to decomposition ofthe active agent, such as oxidative reactions.

Formulations of the present invention may include short-term,rapid-onset, rapid-offset, controlled release, sustained release,delayed release, and pulsatile release formulations, providing theformulations achieve administration of a compound as described herein.See Remington's Pharmaceutical Sciences (18^(th) ed.; Mack PublishingCompany, Eaton, Pa., 1990), herein incorporated by reference in itsentirety.

Pharmaceutical formulations according to the present invention aresuitable for various modes of delivery, including oral, parenteral(including intravenous, intramuscular, subcutaneous, intradermal, andtransdermal), topical (including dermal, buccal, and sublingual), andrectal administration. The most useful and/or beneficial mode ofadministration can vary, especially depending upon the condition of therecipient and the disorder being treated.

The pharmaceutical formulations may be conveniently made available in aunit dosage form, whereby such formulations may be prepared by any ofthe methods generally known in the pharmaceutical arts. Generallyspeaking, such methods of preparation comprise combining (by variousmethods) an active agent, such as the compounds of Formula I accordingto the present invention (or a pharmaceutically acceptable ester, amide,salt, or solvate thereof) with a suitable carrier or other adjuvant,which may consist of one or more ingredients. The combination of theactive ingredient with the one or more adjuvants is then physicallytreated to present the formulation in a suitable form for delivery(e.g., shaping into a tablet or forming an aqueous suspension).

Pharmaceutical formulations according to the present invention suitableas oral dosage may take various foul's, such as tablets, capsules,caplets, and wafers (including rapidly dissolving or effervescing), eachcontaining a predetermined amount of the active agent. The formulationsmay also be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, and as a liquid emulsion(oil-in-water and water-in-oil). The active agent may also be deliveredas a bolus, electuary, or paste. It is generally understood that methodsof preparations of the above dosage forms are generally known in theart, and any such method would be suitable for the preparation of therespective dosage forms for use in delivery of the compounds accordingto the present invention.

A tablet containing a compound according to the present invention may bemanufactured by any standard process readily known to one of skill inthe art, such as, for example, by compression or molding, optionallywith one or more adjuvant or accessory ingredient. The tablets mayoptionally be coated or scored and may be formulated so as to provideslow or controlled release of the active agent.

Solid dosage forms may be formulated so as to provide a delayed releaseof the active agent, such as by application of a coating. Delayedrelease coatings are known in the art, and dosage forms containing suchmay be prepared by any known suitable method. Such methods generallyinclude that, after preparation of the solid dosage form (e.g., a tabletor caplet), a delayed release coating composition is applied.Application can be by methods, such as airless spraying, fluidized bedcoating, use of a coating pan, or the like. Materials for use as adelayed release coating can be polymeric in nature, such as cellulosicmaterial (e.g., cellulose butyrate phthalate, hydroxypropylmethylcellulose phthalate, and carboxymethyl ethylcellulose), andpolymers and copolymers of acrylic acid, methacrylic acid, and estersthereof.

Solid dosage forms according to the present invention may also besustained release (i.e., releasing the active agent over a prolongedperiod of time), and may or may not also be delayed release. Sustainedrelease formulations are known in the art and are generally prepared bydispersing a drug within a matrix of a gradually degradable orhydrolyzable material, such as an insoluble plastic, a hydrophilicpolymer, or a fatty compound. Alternatively, a solid dosage form may becoated with such a material.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions, which may further containadditional agents, such as anti-oxidants, buffers, bacteriostats, andsolutes, which render the formulations isotonic with the blood of theintended recipient. The formulations may include aqueous and non-aqueoussterile suspensions, which contain suspending agents and thickeningagents. Such formulations for patenteral administration may be presentedin unit-dose or multi-dose containers, such as, for example, sealedampoules and viles, and may be stores in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample, water (for injection), immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules, and tablets of the kind previously described.

The compounds according to the present invention may also beadministered transdermally, wherein the active agent is incorporatedinto a laminated structure (generally referred to as a “patch”) that isadapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. Typically, such patches areavailable as single layer “drug-in-adhesive” patches or as multi-layerpatches where the active agent is contained in a layer separate from theadhesive layer. Both types of patches also generally contain a backinglayer and a liner that is removed prior to attachment to the skin of therecipient. Transdermal drug delivery patches may also be comprised of areservoir underlying the backing layer that is separated from the skinof the recipient by a semi-permeable membrane and adhesive layer.Transdermal drug delivery may occur through passive diffusion or may befacilitated using electrotransport or iontophoresis.

Formulations for rectal delivery of the compounds of the presentinvention include rectal suppositories, creams, ointments, and liquids.Suppositories may be presented as the active agent in combination with acarrier generally known in the art, such as polyethylene glycol. Suchdosage forms may be designed to disintegrate rapidly or over an extendedperiod of time, and the time to complete disintegration can range from ashort time, such as about 10 minutes, to an extended period of time,such as about 6 hours.

The compounds of Formula I above may be formulated in compositionsincluding those suitable for oral, buccal, rectal, topical, nasal,ophthalmic, or parenteral (including intraperitoneal, intravenous,subcutaneous, or intramuscular injection) administration. Thecompositions may conveniently be presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Allmethods include the step of bringing a compound of Formula I intoassociation with a carrier that constitutes one or more accessoryingredients. In general, the compositions are prepared by bringing acompound of the invention into association with a liquid carrier to forma solution or a suspension, or alternatively, bringing a compound of theinvention into association with formulation components suitable forforming a solid, optionally a particulate product, and then, ifwarranted, shaping the product into a desired delivery form. Solidformulations of the invention, when particulate, will typically compriseparticles with sizes ranging from about 1 nanometer to about 500microns. In general, for solid formulations intended for intravenousadministration, particles will typically range from about 1 nm to about10 microns in diameter.

The amount of the compound of Formula I in the formulation will varydepending the specific compound selected, dosage form, target patientpopulation, and other considerations, and will be readily determined byone skilled in the art. The amount of the compound of Formula I in theformulation will be that amount necessary to deliver a therapeuticallyeffective amount of the compound to a patient in need thereof to achieveat least one of the therapeutic effects associated with the compounds ofthe invention. In practice, this will vary widely depending upon theparticular compound, its activity, the severity of the condition to betreated, the patient population, the stability of the formulation, andthe like. Compositions will generally contain anywhere from about 1% byweight to about 99% by weight of a compound of the invention, typicallyfrom about 5% to about 70% by weight, and more typically from about 10%to about 50% by weight, and will also depend upon the relative amountsof excipients/additives contained in the composition.

Combinations

In specific embodiments, active agents used in combination withcompounds of the present invention comprise one or more compoundsgenerally recognized as useful for treating the conditions discussedherein. For example, in certain embodiments, the present inventionprovides a method for treating depression comprising administering acombination of a compound of the present invention and one or more knownantidepressants. Antidepressants useful according to the inventioncomprise selective serotonin reuptake inhibitors (SSRIs), tricyclics,serotonin norepinephrine reuptake inhibitors (5-HT-NE dual reuptakeinhibitors), and norepinephrine and dopamine reuptake inhibitors(NDRIs).

In one embodiment, compounds of Formula I may be combined with one ormore compounds that are serotonin reuptake inhibitors. Serotoninreuptake inhibitors increase the extracellular level of the serotonin byinhibiting its reuptake into the presynaptic cell, which increases thelevel of serotonin available to bind to and stimulate the postsynapticreceptor. A significant percentage of bupropion use currently occurs incombination with one or more anti-depressant drugs, most commonly bycombining bupropion with one or more SSRIs. Examples of SSRIs includefluoxetine (PROZAC®) paroxetine (PAXIL®), sertraline (ZOLOFT®),citalopram (CELEXA®), escitalopram (LEXAPRO®), nefazodone (SERZONE®) andfluvoxamine (LUVOX®).

In another embodiment, compounds of Formula I may be combined with oneor more compounds that at least partially inhibit the function ofmonoamine oxidase. Monoamine oxidase inhibitors (MAOIs) comprise a classof compounds understood to act by inhibiting the activity of monoamineoxidase, an enzyme generally found in the brain and liver of the humanbody, which functions to break down monoamine compounds, typicallythrough deamination. There are two isoforms of monoamine oxidaseinhibitors, MAO-A and MAO-B. The MAO-A isoform preferentially deaminatesmonoamines typically occurring as neurotransmitters (e.g., serotonin,melatonin, epinephrine, norepinephrine, and dopamine). Thus, MAOIs havebeen historically prescribed as antidepressants and for treatment ofother social disorders, such as agoraphobia and social anxiety. TheMAO-B isoform preferentially deaminates phenylethylamine and traceamines. Dopamine is equally deaminated by both isoforms. MAOIs may byreversible or non-reversible and may be selective for a specificisoform. For example, the MAOI moclobemide (also known as Manerix orAurorix) is known to be approximately three times more selective forMAO-A than MAO-B.

Any compound generally recognized as being an MAOI may be usefulaccording to the present invention. Non-limiting examples of MAOIsuseful in combination with compounds of the present invention forpreparing compositions according to the invention include the following:isocarboxazid (MARPLAN®); moclobemide (Aurorix, Manerix, or Moclodura);phenelzine (NARDIL®); tranylcypromine (PARNATE®); selegiline (ELDEPRYL®,EMSAM®, or 1-deprenyl); lazabemide; nialamide; iproniazid (marsilid,iprozid, iprozid, rivivol, or propilniazida); iproclozide; toloxatone;harmala; brofaromine (Consonar); benmoxin (Neuralex); and certaintryptamines, such as 5-MeO-DMT (5-Methoxy-N,N-dimethyltryptamine) or5-MeO-AMT (5-methoxy-α-methyltryptamine).

According to still another embodiment of the invention, compounds ofFormula I may be combined with one or more compounds that is anorepinephrine reuptake inhibitor (NRI). NRIs are also known asnoradrenaline reuptake inhibitors (NARIs) and generally function toelevate the level of norepinephrine in the central nervous system (CNS)by inhibiting reuptake of norepinephrine from the synaptic cleft intothe presynaptic neuronal terminal Norepinephrine is a catecholamine andphenylethylamine that functions as a neurotransmitter and is known toaffect many conditions. Any compound typically recognized as inhibitingthe reuptake of norepinephrine in the CNS can be used according to thepresent invention. Non-limiting examples of NRIs useful according to theinvention comprise atomoxetine (STRATTERA®), reboxetine (EDRONAX®,VESTRA®, or NOREBOX®), viloxazine (EMOVIT®, VIVALAN®, VIVARINT®, orVIVILAN®), maprotiline (DEPRILEPT®, LUDIOMIL®, or PSYMION®), bupropion(WELLBUTRIN® or ZYBAN®), and radafaxine.

Further non-limiting examples of specific antidepressants usefulaccording to the invention include tricyclics such as amitriptyline,nortriptyline, and desipramine; serotonin-norepinephrine reuptakeinhibitors such as venlafaxine (EFFEXOR®), duloxetine (CYMBALTA®), andmilnacipran; tetracyclics such as maprotiline and mirtazapine; and otherclasses of compounds, including triazolopyridines such as trazodone.

The above compounds and classes of compounds are only examples of thetypes of active agents that can be used in combination with a compoundof the present invention for the treatment of mood disorders, sleepdisorders, or attention deficit disorders and are not intended to belimiting of the invention. Rather, various further active agents can becombined with one or more compounds of the present invention accordingto the invention. For example, any drug generally recognized as being anantidepressant, antinarcoleptic, or ADHD treatment can be used incombination with one or more compounds of the present invention.Moreover, it is possible according to the invention to combine two ormore additional active agents with a compound of the present inventionfor the treatment of the noted conditions.

Non-limiting examples of further active agents that can be combined withcompounds of the present invention include: mood stabilizers (such aslithium, olanzipine, verapamil, quetiapine, lamotrigine, carbamazepine,valproate, oxcarbazepine, risperidone, aripiprazole, and ziprasidone);antipsychotics (such as haloperidol and other butyrophenones,chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and otherphenothiazines, and clozapine); serotonin receptor antagonist (5-HT2 and5-HT3 antagonists) (such as ondansetron, tropisetron, katenserin,methysergide, cyproheptadine, and pizotifen); serotonin receptoragonists (5-HT1A receptor agonists) (such as buspirone); stimulants[such as caffeine, ADDERALL®, methylphenidate (METADATE®, RITALIN®, orCONCERTA®), pemoline (CYLERT®), or modafinil (PROVIGIL®)]; andgamma-hydroxybutyrate (GHB) (XYREM®). Although the above compounds aredescribed in terms of classes of compounds and specific compounds, it isunderstood that there is substantial overlap between certain classes ofcompounds (such as between mood stabilizers, antipsychotics,antidepressants, and serotonin receptor antagonists). Thus, specificcompounds exemplifying a specific class of compounds may also properlybe identified with one or more further classes of compounds.Accordingly, the above classifications should not be viewed as limitingthe scope of the types of compounds useful in combination with compoundsof the present invention for treating the conditions described herein.

Bupropion is also commonly combined with other therapeutic agents forthe treatment of nicotine addiction. Thus, in one embodiment, a compoundof the present invention is combined with one or more nicotinesubstitutes for the treatment of nicotine addiction. Nicotinicreplacement therapies that may be combined with compounds of the presentinvention include, but are not limited to transdermal nicotine patches(e.g., Habitrol®, Nicoderm CQ®, and Nicotrol®), nicotine gum (e.g.,Nicorette®), nicotine lozenges (e.g., Commit®), nicotine-containingsublingual tablets (e.g., Nicorette®Microtabs), and nicotine nasalsprays or inhalers. Compounds of the present invention may also becombined with one or more nicotinic drugs. One particular class ofnicotinic drugs that may be used with compounds of the present inventionencompasses α-4-β2 nicotinic receptor partial agonists, includingvarenicline (Chantix®). Combinations of compounds of the presentinvention with other therapeutic agents are also included in the presentinvention, wherein the condition to be treated is responsive to theinhibition of dopamine and/or norepinephrine reuptake.

The compound of Formula I and the one or more other therapeutic agentsmay be contained within a single composition or alternatively may beadministered concurrently or sequentially (consecutively) in any order.For sequential administration, each of the compound of Formula I and theone or more other therapeutic agents can be formulated in its ownpharmaceutical composition, each of which is to be administeredsequentially, in any order. Alternatively, the compound of Formula I andthe one or more other therapeutic agents can be formulated together. Thecompositions may be formulated for oral, systemic, topical, intravenous,intraparenteral, intravaginal, intraocular, transbuccal, transmucosal,or transdermal administration.

Methods of Use

In a further embodiment, the present invention provides a method fortreating or delaying the progression of disorders that are alleviated byinhibiting monoamine reuptake in a patient, the method comprisingadministering a therapeutically effective amount of at least onecompound of Formula I to the patient. In particular, the presentinvention relates to the field of treating addiction and depressiveconditions in animals, particularly humans and other mammals, andassociated effects of these conditions. It also may relate to thetreatment of other conditions that may benefit from the inhibition ofmonoamine reuptake. It may particularly relate to the treatment ofconditions that may benefit from one or more of dopamine,norepinephrine, and serotonin reuptake inhibition. In some embodiments,the compounds of the present invention are selective for one or moremonoamine transporter. In some embodiments, the compounds bind morestrongly to the dopamine and norepinephrine transporters than to theserotonin transporters. In preferred embodiments, the compounds bindmore strongly to the dopamine transporters than the norepinephrine orserotonin transporters.

Addiction has its common meaning, e.g., the condition that exists whenan individual persists in the use of a substance despite impairment ordistress related to the use of the substance. In preferred embodiments,the compounds of the present invention show a slow onset and longduration of activity. These features make the compounds of the presentinvention particularly suitable for the treatment of addiction to abusedsubstances, which commonly exhibit a fast onset and/or short duration ofactivity. Administration of the compounds of the present invention tosubjects with addiction to one or more substances may be particularlysuited for the treatment of cocaine, methamphetamine, and nicotineaddiction.

The compounds of the present invention may also be applicable totreating depression and depressive conditions. Depression has its commonmeaning, e.g., a common mental disorder that presents with depressedmood, loss of interest or pleasure, feelings of guilt or low self-worth,disturbed sleep or appetite, low energy, and poor concentration or amental state characterized by a pessimistic sense of inadequacy and adespondent lack of activity. Physical changes, such as insomnia,anorexia, weight loss, and decreased energy and libido can also occur asa result of depression. Depression includes dysthymic disorder ordysthymia, defined as a chronic low-grade depression and majordepression as well as other stages or levels of depression. It alsoincludes post-partum depression.

The compounds of the present invention may also be used for otherconditions that may be responsive to inhibition of reuptake of one ormore monoamines. In some embodiments, the compounds may be used to treatpatients for conditions that are responsive to the inhibition ofdopamine, norepinephrine, and/or serotonin. For example, in someembodiments, compounds of Formula I may be used to treat patients withbipolar disorder, attention deficit disorder (ADD),attention-deficit/hyperactivity disorder (ADHD), hypoactive sexualdesire disorder, antidepressant-induced sexual dysfunction, orgasmicdysfunction, seasonal affective disorder/winter depression, obesity andfood addiction, mania, bulimia and other eating disorders, panicdisorders, obsessive compulsive disorder, schitzophrenia,schitzo-affective disorder, Parkinson's disease, narcolepsy, anxietydisorders, insomnia, chronic pain, migraine headaches, and restless legssyndrome.

The method of treatment generally includes administering atherapeutically effective amount of a compound of Formula I, optionallyin a pharmaceutical composition including one or more pharmaceuticallyacceptable carriers. The therapeutically effective amount is preferablysufficient to inhibit the reuptake of one or more monoamines. Thetherapeutically effective amount is further preferably sufficient tocause some relief to the patient in the symptoms of the disorder forwhich the patient is being treated.

For example, in one embodiment, a method of treating cocaine addictionis provided. In such methods, a therapeutically effective amount of acompound of the present invention to treat a patient with cocaineaddiction may be that amount capable of exerting some dopaminergiceffects. Cocaine functions by inhibiting the reuptake of dopamine byblocking the dopamine transporter that transports excess dopamine backinto the presynaptic cell. It has a fast onset of activity and shortduration. Chronic cocaine use produces a withdrawal syndrome that isassociated with depletion of dopamine and deficits in dopaminergicsignaling. By providing a compound of the present invention with slowonset and long duration of activity, the compound may be able to reversedopaminergic deficits in chronic cocaine users.

A therapeutically effective amount of a compound of the presentinvention to treat a patient with depression may be that amount capableof providing some relief from symptoms such as changes in mood, feelingsof intense sadness and despair, mental slowing, loss of concentration,pessimistic worry, agitation, and self-deprecation and/or from physicalchanges such as insomnia, anorexia and weight loss, and decreased energyand libido. The levels of one or more of dopamine, norepinephrine, andserotonin may be low in subjects with depression and thus, inhibition ofthe reuptake of any of these monoamines by the appropriate transportermay be effective to adjust the monoamine levels and treat the symptomsof depression.

The therapeutically effective dosage amount of any specific formulationwill vary somewhat from drug to drug, patient to patient, and willdepend upon factors such as the condition of the patient and the routeof delivery. When administered conjointly with other pharmaceuticallyactive agents, even less of the compounds of the invention may betherapeutically effective. Further more, the therapeutically effectiveamount may vary depending on the specific condition to be treated.

The compounds of the invention can be administered once or several timesa day. The daily dose can be administered either by a single dose in theform of an individual dosage unit or several smaller dosage units or bymultiple administration of subdivided dosages at certain intervals.Possible routes of delivery include buccally, subcutaneously,transdermally, intramuscularly, intravenously, orally, or by inhalation.

The compounds of the invention may be used with other types of therapy,including those which are non-drug based. For example, addiction iscommonly treated using one or more therapeutics in combination withbehavior therapy. Thus, in some embodiments, the methods of the presentinvention comprise administering to a subject a compound that that iscapable of functioning as a monoamine reuptake inhibitor in conjunctionwith one or more other types of non-drug-based therapy.

EXPERIMENTAL SECTION Example 1 Synthesis

Nuclear magnetic resonance (¹H NMR and ¹³C NMR) spectra were recorded ona 300 MHz (Bruker AVANCE 300) or 500 MHz (Varian Unity ANOVA)spectrometer. Chemical shift data for the proton resonances werereported in parts per million (δ) relative to internal (CH₃)₄Si (δ0.0).Elemental analyses were performed by Atlantic Microlab, Norcross, Ga.Analytical thin-layer chromatography (TLC) was carried out on platesprecoated with silica gel GHLF (250 μM thickness). TLC visualization wasaccomplished with a UV lamp or in an iodine chamber. Allmoisture-sensitive reactions were performed under a positive pressure ofnitrogen maintained by a direct line from a nitrogen source. Anhydroussolvents were purchased from Aldrich Chemical Co. or VWR. The compoundsdescribed herein are referred to using a number-letter combination thatcan be cross-referenced with data presented in Example 2.

a) Synthesis of Compounds of the Present Invention Synthesis of2-(N-tert-Butylamino)-3-chlorobutanophenone (2o)

Step 1. 3′-Chlorobutanophenone (9o). 3-Chlorobenzonitrile 8d (3.0 g,0.022 mol) and THF (75 mL) were placed in a 250 mL flask equipped with amagnetic stir bar. The flask was cooled to 0° C. with an ice-water bath.Propylmagnesium chloride (26.2 mL, 2M in Et₂O) was syringed in over a 10min period. The reaction was stirred under nitrogen at room temperature.After 96 h, the flask was cooled to 0° C. The reaction was quenched byadding 0.1 M hydrochloric acid (75 mL). After stirring for 1 h at roomtemperature, the solution was transferred to a separatory funnel. Water(50 mL) and ammonium hydroxide (2 mL) were added to basify the reaction,and the aqueous layer was extracted three times with methylene chloride.The organic layer was dried (Na₂SO₄) and filtered. The solvent wasremoved under reduced pressure to give 3.51 g (88%) of 90 as alight-yellow oil. ¹H NMR (CDCl₃) δ 7.95 (s, 1H), 7.81-7.87 (d, 1H),7.50-7.56 (d, 1H), 7.38-7.40 (t, 1H), 2.90-2.95 (t, 2H), 1.72-1.81 (m,2H), 0.99-1.05 (t, 3H).

Step 2. 2-Bromo-3′-chlorobutanophenone (10o). Ketone 90 (3.51 g, 0.01mol) and methylene chloride (75 mL) were placed in a 500 mL flaskequipped with a magnetic stir bar. The solution was stirred undernitrogen, and bromine (0.98 mL, 0.019 mol) was syringed into the flask.A small amount of bromine was added initially to catalyze the reaction.After reaction started, the remaining bromine was added over a 10 minperiod. After stirring for 14 h, the solution was transferred to aseparatory funnel. A saturated sodium bicarbonate solution was added tobasify the reaction. The aqueous layer was washed with a 1 M sodiumthiosulfate solution and extracted three times with methylene chloride.The organic layer was dried (Na₂SO₄) and filtered. The solvent wasremoved under reduced pressure to give 5.20 g of an oil. The orange oilwas purified by flash chromatography on silica gel using 5:1hexane/methylene chloride as eluent to afford 4.04 g (80%) of 10o as acolorless oil. ¹H NMR (CDCl₃) δ 8.00 (s, 1H), 7.86-7.91 (d, 1H),7.54-7.59 (d, 1H), 7.41-7.48 (t, 1H), 4.99-5.05 (t, 1H), 2.07-2.30 (m,2H), 1.07-1.12 (t, 3H).

Step 3. 2-(N-tert-Butylamino)-3′-Chlorobutanophenone (2o) Fumarate.Intermediate 10o (3.90 g, 0.015 mol) and tert-butylamine (7.84 mL, 0.075mol) were placed in a sealed tube equipped with a magnetic stir bar. Thetube was sealed and heated at 75° C. with an oil bath. After 2 h, thereaction mixture was cooled to room temperature and transferred to aseparatory funnel. A saturated sodium bicarbonate solution was added tobasify the reaction, and the aqueous layer was extracted with methylenechloride (3×). The organic layer was dried (Na₂SO₄), and the solvent wasremoved under reduced pressure. The oil was dissolved in methanol, andthe solvent was removed under reduced pressure to afford 3.51 g (93%) of2o as a pale-yellow oil. ¹H NMR (CDCl₃) δ 7.95 (s, 1H), 7.84-7.89 (d,1H), 7.53-7.58 (d, 1H), 7.40-7.48 (t, 1H), 4.04-4.10 (m, 1H), 2.04-2.24(m, 2H), 1.02 (s, 9H), 0.92-0.99 (t, 1H). Amine 2o was converted to afumarate salt by adding one equivalent of fumaric acid to an Et₂Osolution of 2o. Recrystallized from methanol and Et₂O afforded 2.64 g of2o•fumarate as a white solid: mp 155-156° C. ¹H NMR (CD₃OD) δ 8.20 (s,1H), 8.10-8.15 (d, 1H), 7.76-7.81 (d, 1H), 7.60-7.68 (t, 1H), 6.70 (s,2H), 5.20-5.25 (t, 1H), 2.01-2.11 (m, 2H), 1.37 (s, 9H), 1.15-1.22 (t,3H). Anal. (C₁₈H₂₄NO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′-chloropentanophenone (2p)

Step 1. 3′-Chloropentanophenone (9p). 3-Chlorobenzonitrile 8d (3.0 g,0.022 mol) and THF (75 mL) were placed in a 250-mL flask equipped with amagnetic stir bar. The flask was cooled to 0° C. with an ice-water bath.Butylmagnesium chloride (26.2 mL, 2 M in THF) was syringed in over a10-min period. The reaction mixture was stirred under nitrogen at roomtemperature. After 96 h, the flask was cooled to 0° C. and quenched byadding 0.1 M hydrochloric acid (75 mL). After stirring for 1 h at roomtemperature, the solution was transferred to a separatory funnel, water(50 mL) and ammonium hydroxide (2 mL) were added to basify the reaction,and the aqueous layer was extracted three times with methylene chloride.The organic layer was dried (Na₂SO₄) and filtered. The solvent wasremoved under reduced pressure to give 4.04 g (94%) of 9p as a lightyellow solid. ¹H NMR (CDCl₃) δ 7.95 (s, 1H), 7.85-7.80 (d, 1H),7.56-7.51 (d, 1H), 7.45-7.38 (t, 1H), 2.98-2.91 (t, 2H), 1.80-1.68 (m,2H), 1.49-1.38 (m, 2H), 1.01-0.92 (t, 3H).

Step 2. 2-Bromo-3′-chloropentanophenone (10p). Ketone 10p (4.04 g, 0.021mol) and methylene chloride (75 mL) were placed in a 500-mL flaskequipped with a magnetic stir bar. The solution was stirred undernitrogen, and bromine (0.98 mL, 19.2 mmol) was syringed into the flask.A small amount of bromine was added initially to catalyze the reaction.After reaction started, the remaining bromine was added over a 10-minperiod. After stirring for 14 h, the solution was transferred to aseparatory funnel. A saturated sodium bicarbonate solution was added tobasify the reaction. The mixture was extracted with methylene chloride(3×). The organic layer was dried (Na₂SO₄) and filtered. The solvent wasremoved under reduced pressure to give 6.02 g of an oil. The orange oilwas purified by flash chromatography on silica gel (5:1 hexane-methylenechloride) to afford 3.69 g (65%) of 10p as a colorless oil. ¹H NMR(CDCl₃) δ 7.97 (s, 1H), 7.90-7.85 (d, 1H), 7.59-7.54 (d, 1H), 7.47-7.40(t, 1H), 5.09-5.02 (t, 1H), 2.22-2.07 (m, 2H), 1.65-1.39 (m, 2H),1.05-0.95 (t, 3H).

Step 3. 2-(N-tert-Butylamino)-3′-chloropentanophenone (2p) Fumarate.Intermediate 10p (3.60 g, 0.013 mol) and tert-butylamine (6.86 mL, 65.3mmol) were placed in a pressure tube equipped with a magnetic stir bar.The tube was sealed and heated at 75° C. with an oil bath. After 9 h,the reaction mixture was cooled to room temperature and transferred to aseparatory funnel. A saturated sodium bicarbonate solution was added tobasify the reaction, and the aqueous layer was extracted with methylenechloride (3×). The organic layer was dried (Na₂SO₄) and filtered. Thesolvent was removed under reduced pressure. The resulting oil wasdissolved in methanol, and the solvent was removed under reducedpressure to afford 3.25 g (93%) of 2p as a pale yellow oil. ¹H NMR(CDCl₃) δ 7.99 (s, 1H), 7.90-7.85 (d, 1H), 7.60-7.55 (d, 1H), 7.50-7.42(t, 1H), 4.15-4.09 (m, 1H), 1.60-1.43 (m, 2H), 1.43-1.25 (m, 2H), 1.02(s, 9H), 0.94-0.88 (t, 3H). Amine 2p was converted to a fumarate saltusing the procedure described for 2b. Recrystallization from methanoland Et₂O afforded 2.64 g of 2p•fumarate as a white solid: mp 159-160° C.¹H NMR (CDCl₃/CD₃OD) δ 8.05 (s, 1H), 7.98-7.93 (d, 1H), 7.71-7.66 (d,1H), 7.60-7.52 (t, 1H), 6.77 (s, 2H), 4.74-4.69 (t, 1H), 1.91-1.69 (m,2H), 1.39-1.17 (m, 2H), 1.25 (s, 9H), 0.91-0.85 (t, 3H). Anal.(C₁₉H₂₆NO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′-chlorohexanophenone (2q)

Step 1. 3′-Chlorohexanophenone (9q). 3-Chlorobenzonitrile 8d (5 g, 0.036mol) and dry THF (110 mL) were placed in a flask equipped with amagnetic stir bar. The flask was cooled to 0° C. with an ice-water bathand stirred under nitrogen. Pentylmagnesium bromide (22 mL, 2 M in Et₂O)was syringed in over a 10-min period. After 1 h, the reaction mixturewas warmed to room temperature. After 6 days, the flask was cooled to 0°C., and cold 1 M hydrochloric acid (75 mL) was added slowly. Thereaction mixture was allowed to stir at room temperature overnight. Thesolution was transferred to a separatory funnel and basified withammonium hydroxide. The aqueous layer was extracted three times withethyl acetate. The organic layer was dried (Na₂SO₄) and filtered. Thesolvent was removed under reduced pressure to give 7.55 g (99%) of 9q asa light yellow solid. ¹H NMR (CDCl₃) δ 7.93 (s, 1H), 7.85-7.81 (d, 1H),7.55-7.51 (d, 1H), 7.43-7.37 (t, 1H), 2.97-2.91 (t, 2H), 1.76-1.68 (m,2H), 1.40-1.33 (m, 4H), 0.94-0.89 (m, 3H).

Step 2. 2-Bromo-3′-chlorohexanophenone (10q). Ketone 9q (7.55 g, 0.036mol) was dissolved in chloroform (200 mL) and stirred under nitrogen.Bromine (1.9 mL, 36 mmol) was syringed into the flask. The flask washeated briefly with a heat gun to initiate the reaction (approx. 1 min).The HBr evolved was allowed to escape via a syringe needle placed in therubber septa. After stirring 5 h, the solution was transferred to aseparatory funnel. The reaction mixture was basified with saturatedsodium bicarbonate, and the aqueous layer was extracted with chloroform(3×). The organic layer was dried (Na₂SO₄) and filtered. The solvent wasremoved under reduced pressure to afford 10.66 g (100%) of 10q as ayellow oil. ¹H NMR (CDCl₃) δ 7.99 (s, 1H), 7.91-7.86 (d, 1H), 7.60-7.55(d, 1H), 7.47-7.40 (t, 1H), 5.08-5.02 (t, 1H), 2.21-2.09 (m, 2H),1.55-1.34 (m, 4H), 0.96-0.90 (t, 3H).

Step 3. 2-(N-tert-Butylamino)-3′-chlorohexanophenone (2q) Fumarate.Intermediate 10q (10.66 g, 0.037 mol) and tert-butylamine (20 mL) wereplaced in a flask equipped with a magnetic stir bar and a refluxcondenser. The reaction mixture was refluxed under nitrogen at 60° C.After 26 h, the reaction mixture was cooled to room temperature,basified with saturated sodium bicarbonate, and extracted with methylenechloride (3×). The organic layer was dried (Na₂SO₄) and filtered. Thesolvent was removed under reduced pressure to give about 10 g of an oil.The orange oil was purified by flash chromatography [CMA 80 (80% CH₂Cl₂,18% CH₃OH, 2% conc. NH₄OH)] to afford 2.75 g (27%) of 2q as a lightyellow oil. ¹H NMR (CDCl₃) δ 7.96 (s, 1H), 7.88-7.84 (d, 1H), 7.58-7.54(d, 1H), 7.47-7.41 (t, 1H), 4.12-4.08 (m, 1H), 1.60-1.45 (m, 2H),1.39-1.25 (m, 4H), 1.02 (s, 9H), 0.92-0.87 (t, 3H). Amine 2q wasconverted to a fumarate salt using the procedure described for 2b.Recrystallization from methanol and ethyl acetate to afford 3.06 g of2q•fumarate as a white crystalline solid: mp 172-173° C. ¹H NMR (CD₃OD)δ 8.19 (s, 1H), 8.14-8.11 (d, 1H), 7.80-7.77 (d, 1H), 7.67-7.60 (t, 1H),6.70 (s, 2H), 5.23-5.19 (t, 1H), 2.01-1.95 (m, 2H), 1.36 (s, 9H),1.39-1.19 (m, 4H), 0.86-0.81 (t, 3H). Anal. (C₂₀H₂₈ClNO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′-chloroheptanophenone (2r)

Step 1. 3′-Chloroheptanophenone (9r). 3-Chlorobenzonitrile 8d (5 g,0.036 mol) and dry THF (100 mL) were placed in a flask equipped with amagnetic stir bar. The flask was cooled to 0° C. with an ice-water bathand stirred under nitrogen. Hexylmagnesium bromide (22 mL, 2 M in Et₂O)was syringed in over a 10-min period. After 1 h, the reaction mixturewas warmed to room temperature. After 6 days, the flask was cooled to 0°C., and cold 1 M hydrochloric acid (75 mL) was added slowly. Thereaction mixture was allowed to stir at room temperature overnight. Thesolution was transferred to a separatory funnel and basified withammonium hydroxide. The aqueous layer was extracted three times withethyl acetate. The organic layer was dried (Na₂SO₄) and filtered. Thesolvent was removed under reduced pressure to give 7.74 g (95%) of 9r asa light yellow solid. ¹H NMR (CDCl₃) δ 7.93 (s, 1H), 7.85-7.81 (d, 1H),7.55-7.51 (d, 1H), 7.43-7.37 (t, 1H), 2.97-2.91 (t, 2H), 1.78-1.67 (m,2H), 1.43-1.23 (m, 6H), 0.92-0.87 (t, 3H).

Step 2. 2-Bromo-3′-chloroheptanophenone (10r). Ketone 9r (7.74 g, 0.034mol) was dissolved in chloroform (200 mL) and stirred under nitrogen.Bromine (1.8 mL, 34 mmol) was syringed into the flask. The flask washeated briefly with a heat gun to initiate the reaction (approx. 1 min).The HBr evolved was allowed to escape via a syringe needle placed in therubber septa. After stirring 5 h, the solution was transferred to aseparatory funnel. The reaction mixture was basified with saturatedsodium bicarbonate, and the resulting aqueous layer was extracted threetimes with chloroform. The organic layer was dried (Na₂SO₄) andfiltered. The solvent was removed under reduced pressure to afford 10.42g (100%) of 10b as a yellow oil. ¹H NMR (CDCl₃) δ 7.99 (s, 1H),7.90-7.87 (d, 1H), 7.59-7.55 (d, 1H), 7.47-7.40 (t, 1H), 5.08-5.02 (t,1H), 2.22-2.09 (m, 2H), 1.56-1.33 (m, 6H), 0.92-0.87 (m, 3H).

Step 3. 2-(N-tert-Butylamino)-3′-chloroheptanophenone (2r) Fumarate.Intermediate 10r (10.42 g, 0.034 mol) and tert-butylamine (18 mL) wereplaced in a flask equipped with a magnetic stir bar and a refluxcondenser. The reaction mixture was refluxed under nitrogen at 60° C.After 16 h, the reaction mixture was cooled to room temperature,basified with saturated sodium bicarbonate, and extracted three timeswith methylene chloride. The organic layer was dried (Na₂SO₄) andfiltered. The solvent was removed under reduced pressure to give about10 g of an oil. The orange oil was purified by flash chromatography [CMA80 (80% CH₂Cl₂, 18% CH₃OH, 2% conc. NH₄OH)] to afford 3.08 g (30%) of 2ras a light yellow oil. ¹H NMR (CDCl₃) δ 7.96 (s, 1H), 7.87-7.84 (d, 1H),7.58-7.54 (d, 1H), 7.47-7.41 (t, 1H), 4.12-4.09 (m, 1H), 1.57-1.45 (m,2H), 1.34-1.24 (m, 6H), 1.02 (s, 9H), 0.89-0.84 (t, 3H). Amine 2r wasconverted to a fumarate salt using the procedure described for 2b.Recrystallization from ethyl acetate afforded 3.02 g of 2r•fumarate as awhite crystalline solid: mp 162-163° C. ¹H NMR (CD₃OD) δ 8.19 (s, 1H),8.13-8.09 (d, 1H), 7.80-7.76 (d, 1H), 7.66-7.60 (t, 1H), 6.69 (s, 2H),5.19-5.15 (t, 1H), 2.01-1.91 (m, 2H), 1.34 (s, 9H), 1.25-1.15 (m, 6H),0.86-0.81 (m, 3H). Anal. (C₂₁H₃₀ClNO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′-chlorooctanophenone (2s)

Step 1. 3′-Chlorooctanophenone (9s). To a flame-dried flask equippedwith a magnetic stir bar, 1-iodoheptane (14.46 g, 0.064 mol) was addedin 100 mL of the solvent system. The solvent was 3:2 by volume of dryn-pentane-dry Et₂O (60 mL:40 mL). The solution was cooled to −78° C. andstirred under a nitrogen atmosphere. tert-Butyllithium (2.2 equivalents,75 mL, 1.7 M in pentane) were added dropwise over two 30-min periodsusing a syringe pump. The reaction turned light yellow, and a whiteprecipitate formed. After the addition was complete, the solution waswarmed to room temperature. After warming for 30 min, the reactionmixture was cooled to −78° C., and 3′-chlorobenzonitrile 8b (10 g, 0.073mol) was added. After stirring for 10 min, the reaction mixture waswarmed to room temperature. The reaction turned yellow-orange. After 3h, the solvent was removed under nitrogen, and 1 M hydrochloric acid (50mL) was added. After stirring for 30 min, the solution was transferredto a separatory funnel. The aqueous layer was extracted three times withethyl acetate. The organic layer was dried (Na₂SO₄) and filtered. Thesolvent was removed under reduced pressure to afford 17 g of an oil. Theorange oil was purified by flash chromatography (6:1 hexane-methylenechloride) to afford 15.8 g (91%) of 9s as a light yellow oil. ¹H NMR(CDCl₃) δ 7.93 (s, 1H), 7.85-7.81 (d, 1H), 7.55-7.50 (d, 1H), 7.43-7.37(t, 1H), 2.97-2.91 (t, 2H), 1.76-1.70 (m, 2H), 1.41-1.29 (m, 8H),0.86-0.91 (t, 3H).

Step 2. 2-Bromo-3′-chlorooctanophenone (10s). In a flask equipped with amagnetic stir bar, ketone 9s (15 g, 0.063 mol) was dissolved inchloroform (200 mL) and stirred under nitrogen. Bromine (3.23 mL, 63mmol) was syringed in over a short period of time. The reaction mixtureinitially turned dark orange, but the color dissipated over time. Thereaction mixture was stirred under nitrogen, and the hydrogen bromidegas evolved in the reaction mixture was allowed to escape into the hoodvia a syringe needle placed into the rubber septa. After 2 h, thereaction mixture was transferred to a separatory funnel, basified withsaturated sodium bicarbonate, and extracted three times with chloroform.The organic layer was dried (Na₂SO₄) and filtered. The solvent wasremoved under reduced pressure to give 19.95 g (100%) of 10s as anorange oil. ¹H NMR (CDCl₃) δ 7.99 (s, 1H), 7.90-7.87 (d, 1H), 7.58-7.54(d, 1H), 7.43-7.36 (t, 1H), 5.08-5.02 (t, 1H), 2.19-2.14 (m, 2H),1.55-1.30 (m, 8H), 0.91-0.86 (m, 3H).

Step 3. 2-(N-tert-Butylamino)-3′-chlorooctanophenone (2s) Fumarate.Intermediate 10s (19 g, 0.060 mol) and tert-butylamine (63 mL) wereplaced in a flask equipped with a magnetic stir bar and a refluxcondenser. The reaction mixture was refluxed under nitrogen at 60° C.After 24 h, the reaction mixture was cooled to room temperature,basified with saturated sodium bicarbonate solution, and extracted threetimes with methylene chloride. The organic layer was dried (Na₂SO₄) andfiltered. The solvent was removed under reduced pressure to give 17.2 g(93%) of 2s as a dark orange oil. The orange oil was used withoutfurther purification. ¹H NMR (CDCl₃) δ 7.96 (s, 1H), 7.87-7.82 (d, 1H),7.58-7.54 (d, 1H), 7.37-7.31 (t, 1H), 4.13-4.08 (m, 1H), 1.54-1.17 (m,10H), 1.02 (s, 9H), 0.89-0.83 (t, 3H). Amine 2s was converted to afumarate salt using the procedure described for 2b. Recrystallizationfrom methanol and Et₂O afforded 9.61 g of 2s•fumarate as a whitecrystalline solid: mp 139-140° C. ¹H NMR (CD₃OD) δ 8.18 (s, 1H),8.13-8.09 (d, 1H), 7.79-7.75 (d, 1H), 7.65-7.59 (t, 1H), 6.69 (s, 2H),5.23-5.19 (m, 1H), 2.00-1.97 (m, 2H), 1.35 (s, 9H), 1.19-1.10 (m, 8H),0.82-0.79 (m, 3H). Anal. (C₂₂H₃₂ClNO₅.0.5 H₂O)C, H, N.

Synthesis of2-(N-tert-Butylamino)-3′-chlorophenyl-4-methylpentanophenone (2t)

Step 1. 3′-Chlorophenyl-4-methylpentanophenone (9t).3′-Chlorobenzonitrile 8a (4.5 g, 0.033 mol) and tetrahydrofuran (dry,150 mL) were place in a flask equipped with a magnetic stir bar. TheGrignard reagent (CH₃)₂CHCH₂MgBr (5.8 g, 0.033 mol) was added, and thereaction mixture was stirred under nitrogen for 72 h. The reactionmixture became orange in color. A solution of 1 M hydrochloric acid (20mL) was added, and the reaction mixture was stirred overnight. Theyellow solution was transferred to a separatory funnel, a saturatedsodium bicarbonate solution was added to basify the reaction, and theaqueous layer was extracted three times with methylene chloride. Theorganic layer was dried (Na₂SO₄) and filtered. The solvent was removedunder reduced pressure to give 4.5 g of an oil. The orange oil waspurified by flash chromatography (7:1 hexane-methylene chloride) toafford 2.20 g (32%) of 9t as a pale yellow oil. ¹H NMR (CDCl₃) δ 7.92(s, 1H), 7.85-7.81 (d, 1H), 7.55-7.51 (d, 1H), 7.46-7.38 (t, 1H),2.97-2.91 (t, 2H), 1.71-1.59 (m, 3H), 0.96-0.94 (d, 6H). (Note: TheGrignard reagent was made by adding the alkyl bromide and magnesiumtogether in tetrahydrofuran).

Step 2. 2-Bromo-3′-chlorophenyl-4-methylpentanophenone (10t). Ketone 9t(2.2 g, 0.01 mol) and methylene chloride (150 mL) were placed in a500-mL flask equipped with a magnetic stir bar. Bromine (0.53 mL, 10.4mmol) was syringed in over a short period of time. The reaction mixtureinitially turned dark orange, but the color dissipated over time. Thereaction was stirred under nitrogen, and the hydrogen bromide gasevolved in the reaction was allowed to escape. After 4 h, the reactionmixture was transferred to a separatory funnel and basified with asaturated sodium bicarbonate solution. The aqueous layer was extractedthree times with methylene chloride. The organic layer was dried(Na₂SO₄) and filtered. The solvent was removed under reduced pressure togive 2.92 g of an oil. The orange oil was purified by flashchromatography (7:1 hexane-methylene chloride) to afford 2.42 g (81%) of10t as a colorless oil. ¹H NMR (CDCl₃) δ 7.99 (s, 1H), 7.91-7.87 (d,1H), 7.59-7.55 (d, 1H), 7.47-7.41 (t, 1H), 5.16-5.10 (t, 1H), 2.15-1.76(m, 3H), 1.00-0.97 (d, 6H).

Step 3. 2-(N-tert-Butylamino)-3′-chlorophenyl-4-methylpentanophenone(2t) Fumarate. Intermediate 10t (2.42 g, 0.084 mol) and tert-butylamine(8.82 mL, 84 mmol) were placed in a pressure tube equipped with amagnetic stir bar. The tube was sealed, and the reaction mixture wasstirred at 80° C. for 12 h. A white precipitate formed. The reactionmixture was cooled and transferred to a separatory funnel. The reactionmixture was basified with a saturated sodium bicarbonate solution, andthe aqueous layer was extracted three times with methylene chloride. Theorganic layer was dried (Na₂SO₄) and filtered. The solvent was removedunder reduced pressure to give 2.30 g of an oil. The yellowish oil waspurified by flash chromatography [7:1 hexane-(9:1 Et₂O-Et₃N)] to afford800 mg (34%) of 2q as a colorless oil. ¹H NMR (CDCl₃) δ 7.95 (s, 1H),7.88-7.84 (d, 1H), 7.58-7.54 (d, 1H), 7.47-7.41 (t, 1H), 4.20-4.14 (m,1H), 1.26-1.19 (m, 3H), 1.02 (s, 9H), 0.82-0.79 (d, 6H). Amine 2t wasconverted to a fumarate salt using the procedure described for 2b.Recrystallization from Et₂O afforded 728 mg of 2t•fumarate as a whitesolid: mp 172-174° C. ¹H NMR (CD₃OD) δ 8.04 (s, 1H), 7.99-7.95 (d, 1H),7.73-7.69 (d, 1H), 7.62-7.54 (t, 1H), 6.76 (s, 2H), 1.66-1.57 (m, 3H),1.29 (s, 9H), 1.10-1.07 (d, 3H), 0.94-0.91 (d, 3H). Anal.(C₂₀H₂₈ClNO₅.0.25 H₂O)C, H, N.

Synthesis of2-(N-tert-Butylamino)-3′-chlorophenyl-4-cyclohexylbutanophenone (2u)

Step 1. 1-Iodo-3-cyclohexylpropane. 1-Chloro-3-cyclohexylpropane (6 mL,37 mmol) and sodium iodide (5.6 g, 0.037 mol) were dissolved in acetone(200 mL) in a 500-mL flask equipped with a magnetic stir bar. Thereaction mixture was refluxed 72 h and cooled. The white precipitate wasfiltered, and the solvent was removed under reduced pressure. The yellowsolution was transferred to a separatory funnel and 1 M sodiumthiosulfate added. The aqueous layer was extracted three times withmethylene chloride. The organic layer was dried (Na₂SO₄) and filtered.The solvent was removed under reduced pressure to afford 8.20 g (85%) ofproduct as a light yellow oil. ¹H NMR (CDCl₃) δ 3.20-3.14 (t, 2H),1.89-1.65 (m, 7H), 1.34-1.24 (m, 6), 0.95-0.86 (m, 2H).

Step 2. 3′-Chlorophenyl-4-cyclohexybutanophenone (9u). To a flame-driedflask, 1-iodo-3-cyclohexylpropane (8.20 g, 0.033 mol) was dissolved (100mL) in 3:2 by volume of dry n-pentane-dry Et₂O. The solution was cooledto −78° C. and stirred with a magnetic stir bar. tert-Butyllithium (2.1equivalents, 41 mL, 1.7 M in pentane) was added dropwise over a 30-minperiod using a syringe pump. The reaction mixture turned light yellow,and a white precipitate formed. After the addition was complete, thereaction mixture was stirred for 5 min. The solution was warmed to roomtemperature and stirred for 45 min. The reaction mixture was cooled to−78° C., and 3′-chlorobenzonitrile 8a (4.5 g, 0.033 mol) was added.After stirring for 10 min, the reaction mixture was warmed to roomtemperature. The reaction turns orange. After 16 h, the solvent wasremoved under nitrogen. Saturated ammonium chloride (20 mL) was added.After 10 min, 1 M hydrochloric acid (35 mL) was added. The solution wastransferred to a separatory funnel. The aqueous layer was extractedthree times with methylene chloride. The organic layer was dried(Na₂SO₄) and filtered. The solvent was removed under reduced pressure toafford 10.78 g of an oil. The orange oil was purified by flashchromatography (11:1 hexane-ethyl acetate) to afford 4.1 g (47%) of 9uas a colorless oil. ¹H NMR (CDCl₃) δ 7.92 (s, 1H), 7.84-7.81 (d, 1H),7.54-7.51 (d, 1H), 7.43-7.37 (t, 1H), 2.95-2.88 (t, 2H), 1.81-1.68 (m,7H), 1.29-1.16 (m, 6H), 0.95-0.86 (m, 2H).

Step 3. 2-Bromo-3′-chlorophenyl-4-cyclohexylbutanophenone (10u). Ketone9u (3.97 g, 0.015 mol) and methylene chloride (100 mL) were placed in a500-mL flask equipped with a magnetic stir bar. Bromine (0.77 mL, 15mmol) was syringed in over a short period of time. The reaction mixtureinitially turned dark orange, but the color dissipated over time. Thereaction mixture was stirred under nitrogen, and the hydrogen bromidegas evolved in the reaction was allowed to escape into the hood. After 4h, the reaction mixture was transferred to a separatory funnel andbasified with a saturated sodium bicarbonate solution. After theaddition of a 1 M sodium thiosulfate solution, the aqueous layer wasextracted three times with methylene chloride. The organic layer wasdried (Na₂SO₄) and filtered. The solvent was removed under reducedpressure to give 4.79 g of an oil. The orange oil was purified by flashchromatography (5:1 hexane-methylene chloride) to afford 3.79 g (74%) of10u as a light yellow oil. ¹H NMR (CDCl₃) δ 7.98 (s, 1H), 7.91-7.86 (d,1H), 7.59-7.54 (d, 1H), 7.47-7.40 (t, 1H), 5.04-4.98 (t, 1H), 2.23-2.10(m, 2H), 1.74-1.68 (m, 5H), 1.34-1.18 (m, 6H), 0.93-0.89 (m, 2H).

Step 4. 2-(N-tert-Butylamino)-3′-chlorophenyl-4-cyclohexylbutanophenone(2u). Intermediate 10u (2.56 g, 0.0075 mol) and tert-butylamine (7.83mL, 75 mmol) were placed in a pressure tube equipped with a magneticstir bar. The tube was sealed, and the reaction mixture was stirred at75° C. for 5 h. A white precipitate formed. The reaction was transferredto a separatory funnel and basified with a saturated sodium bicarbonatesolution. The aqueous layer was extracted three times with methylenechloride. The organic layer was dried (Na₂SO₄) and filtered. The solventwas removed under reduced pressure to give 2.10 g (84%) of 2u as a lightyellow oil. ¹H NMR (CDCl₃) δ 7.95 (s, 1H), 7.87-7.83 (d, 1H), 7.58-7.54(d, 1H), 7.47-7.40 (t, 1H), 4.09-4.06 (m, 1H), 1.67-1.63 (m, 7H),1.33-1.16 (m, 6H), 1.01 (s, 9H), 0.88-0.83 (m, 2H). Amine 2u wasconverted to a fumarate salt using the procedure described for 2b.Recrystallization from isopropanol and hexane afforded 1.16 g of2u•fumarate as a white solid: mp 150-152° C. ¹H NMR (CD₃OD) δ 8.17 (s,1H), 8.14-8.09 (d, 1H), 7.81-7.76 (d, 1H), 7.67-7.60 (t, 1H), 6.68 (s,2H), 5.22-5.17 (m, 1H), 2.04-1.95 (m, 2H), 1.62-1.52 (m, 5H), 1.34 (s,9H), 1.20-1.05 (m, 6H), 0.85-0.70 (m, 2H). Anal. (C₂₄H₃₄ClNO₅) C, H, N.

Synthesis of 2-(N-Cyclopropylamino)-3′-chloropropiophenone (2x)

2-(N-Cyclopropylamino)-3′-chloropropiophenone (2x) Hydrochloride. Asolution of 2-bromo-1-(3-chlorophenyl)propanol (14.7 g, 59.3 mmol) andcyclopropylamine (5.2 mL, 75.0 mmol) in THF (300 mL) was sealed in aglass reactor with Teflon cap and heated to 50° C. for 18 h. Thereaction mixture was concentrated and the residue was taken up intoethyl acetate and washed with saturated aqueous NaHCO₃, water and brine,dried (MgSO₄) and concentrated. The crude product was purified byautomated flash chromatography (silica gel, 4/1 hexane/ethyl acetate) toyield 2.77 g (21%) of orange oil. This material was dissolved intodiethyl ether (250 mL and treated with 4 N HCl in dioxane (16 mL, 64mmol); the mixture stirred overnight at room temperature. The resultingsolids were filtered and recrystallized (methanol/ether) to yield 1.40 g(43%) of pure 2x•hydrochloride. mp 181-183° C. (dec.); ¹H NMR (CD₃OD 300MHz) δ 8.10 (s, 1H), 8.03 (d, 1H, J=9 Hz), 7.76 (d, 1H, J=3 Hz), 7.62(t, 1H, J=6 Hz, 9 Hz), 5.30-5.27 (m, 1H), 2.85-2.77 (m, 1H), 1.62 (d,3H, J=6 Hz), 0.97-0.93 (m, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 135.1, 133.2,130.0, 128.4, 126.4, 98.4, 58.1, 28.7, 19.6, 8.6, 6.6, 6.3; ESI-MS,calculated for C₁₂H₁₄ClNO (M+H)⁺224.7; observed 224.1. Anal.(C₁₂H₁₅ClNO₅.0.25 H₂O)C, H, N.

Synthesis of 2-(N-Cyclobutylamino)-3′-chloropropiophenone (2y)

2-(N-Cyclobutylamino)-3′-chloropropiophenone (2y) Hydrochloride.2-Bromo-1-(3-chlorophenyl)propan-1-one (250 mg, 1.01 mmol) was dissolvedin dry ether (1 mL), and the solution was chilled to 0° C.Cyclobutylamine (0.19 mL, 2.22 mmol) was then added all at once and thereaction mixture was allowed to warm to room temperature and stirovernight. The reaction mixture was poured into an Erlenmeyer flaskcontaining 10% aqueous HCl and EtOAc, and stirred for 10 min. Thebiphasic mixture was partitioned in a separatory funnel. The aqueouslayer was extracted twice with EtOAc and then basified to pH 8-9 withsaturated aqueous Na₂CO₃. The basified aqueous layer was extracted twicewith ether and the combined organic extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated to approximately half theoriginal volume. (Caution: Do not concentrate to dryness or the compoundwill decompose). To the stirring ether solution was slowly added 1 MHCl/Et₂O until the solid stopped precipitating out of solution(typically 0.5 to 1 mL was needed). After stirring for 3 h, the solidwas filtered, washed with ether, and dried. In order to remove theunreacted cyclobutylamine hydrochloride, the crude solid was thenrecrystallized from MeOH/ether and left to sit in a freezer overnight.The solid was then filtered, washed with ether, and dried to afford 60.1mg (22% yield) of 2y•hydrochloride as a white flaky solid. mp 186-187°C. ¹H NMR (CD₃OD, 300 MHz) δ 8.09 (s, 1H), 8.02 (d, J=9.0 Hz, 1H),7.77-7.74 (m, 1H), 7.60 (t, J=15.0, 9.0 Hz, 1H), 5.08 (q, J=21.0, 15.0,6.0 Hz, 1H), 3.94-3.82 (m, 1H), 2.38-2.20 (m, 4H), 1.97-1.85 (m, 2H),1.55 (d, J=6.0 Hz, 3H); ¹³C NMR (CD₃OD, 75 MHz) ppm 196.1, 136.7, 135.9,132.1, 129.7, 128.4, 57.7, 51.7, 28.1, 27.8, 16.5, 15.8; Anal.(C₁₃H₁₇Cl₂NO.0.5H₂O)C, H, N.

Synthesis of 2-(N-Cyclopentylamino)-3′-chloropropiophenone (2z)

Sodium bicarbonate (6.0 g, 0.071 mol) was suspended in a solution of2-bromo-1-(3-chlorophenyl)propanone (6.0 g, 0.024 mol) in acetonitrile(30 mL). Cyclopentylamine (3.88 g, 0.012 mol) was added and the mixturestirred at ambient temperature for 6 h. The mixture was carefully pouredinto 10% hydrochloric acid (50 mL) and ethyl acetate (50 mL). Aftermixing, the aqueous layer was separated, washed with ethyl acetate (25mL), and made alkaline with conc. NH₄OH-water (1:1) mixture. The mixturewas extracted with Et₂O (2×100 mL), and the combined ethereal extractswere dried (K₂CO₃) and filtered. The solvent was removed to give 6.4 gof yellow oil. The fumarate salt 2z•fumarate was formed andrecrystallized form methanol-Et₂O to give a white solid: mp 171-173°C.(dec). ¹H NMR (D₆MSO) δ 9.76 (bs, 1H), 8.10 (s, 1H), 8.03 (d, 1H, J=6Hz), 7.77 (d, 1H, J=6 Hz), 7.61 (t, 1H, J=6 Hz), 6.54 (s, 2H), 4.82 (q,1H, J=Hz), 3.27 (m, 1H), 1.80-1.46 (m, 8H), 1.32 (d, 3H, J=9 Hz). Anal.(C₁₈H₂₂ClNO₅) C, H, N.

Synthesis of 2-(tert-Butylamino)-3′,4′-dichlorobutyrophenone (2aa)

Step 1. 3′,4′-Dichlorobutyrophenone (9aa). To a solution of 3.00 g(0.017 mol) of 8e in 40 mL of dry tetrahydrofuran cooled to 0° C. wasadded dropwise 21 mL (2.0 M in Et₂O) of propylmagnesium chloride. Thereaction solution was allowed to warm to room temperature and stirred atroom temperature for 144 h under nitrogen. The reaction solution wascooled to 0° C. and 150 mL of a 5% aqueous hydrochloric acid solutionwas added dropwise. After stirring overnight at room temperature, thereaction mixture was quenched with a saturated aqueous sodiumbicarbonate solution, and the product was extracted with methylenechloride, dried (Na₂SO₄), and filtered. The solvent was removed, and theresulting residue was dried briefly under high vacuum to give 3.87 g ofa brown oil. Purification by flash chromatography (silica, 5:1hexane-methylene chloride) gave 3.15 g (83%) of 9aa as a yellow oil. ¹HNMR (CDCl₃) δ 8.03 (s, 1H), 7.80-7.76 (dd, 1H), 7.54 (d, 1H), 2.91 (t,2H), 1.84-1.69 (m, 2H), 1.00 (t, 3H).

Step 2. 2-Bromo-3′,4′-dichlorobutyrophenone (10aa). To a solution of3.91 g (0.018 mol) of 9aa in 70 mL of methylene chloride was added tendrops of bromine. After stirring at room temperature under nitrogen forseveral minutes, the characteristic red color of bromine disappearedindicating initiation of the reaction. The remainder of the 1 mL (18.30mmol) of bromine was added dropwise and the reaction solution wasallowed to stir at room temperature under nitrogen for 9.5 h. Thereaction solution was quenched and brought to a pH of 9 with a saturatedaqueous solution of sodium bicarbonate and solid sodium bicarbonate. Theproduct was extracted with methylene chloride, dried (Na₂SO₄), andfiltered. The solvent was removed, and the resulting residue was driedbriefly under high vacuum to give 5.62 g (>100%) of 10aa as an orangeoil. ¹H NMR (CDCl₃) δ 8.10 (s, 1H), 7.86-7.82 (dd, 1H), 7.57 (d, 1H),4.95 (t, 1H), 2.30-2.07 (m, 2H), 1.09 (t, 3H).

Step 3. 2-(tert-Butylamino)-3′,4′-dichlorobutyrophenone (2aa) Fumarate.To a pressure tube was transferred 5.49 g (0.019 mol) of 10aa with aminimal amount of methylene chloride. Most of the methylene chloride wasremoved via positive nitrogen flow, 29 mL (278.21 mmol) oftert-butylamine was added in one portion, and the tube was sealed andplaced in an oil bath heated to 55° C. After stirring at 55° C. for 15h, the reaction mixture was allowed to cool to room temperature. Thereaction mixture was quenched and brought to pH 10 with a saturatedaqueous solution of sodium bicarbonate, and the product was extractedwith methylene chloride, dried (Na₂SO₄), and filtered. The solvent wasremoved, and the resulting residue was dried briefly under high vacuumto give 5.55 g of a brown oil. Purification by flash chromatography(silica, 9:1:50 Et₂O-Et₃N-hexane) gave 3.88 g (73%) of 2aa as an orangeoil. ¹H NMR (CDCl₃) δ 8.08 (s, 1H), 7.85-7.80 (dd, 1H), 7.58 (d, 1H),4.04-3.99 (m, 1H), 1.70-1.61 (m, 1H), 1.40-1.35 (m, 1H), 1.02 (s, 9H),0.96 (t, 3H). To a solution of 3.30 g (0.013 mol) of 2aa in methylenechloride-methanol was added 1.48 g (0.013 mol) of fumaric acid. Thereaction solution was allowed to stir for 15 min, and the solvent wasremoved in vacuo leaving a white solid. Recrystallization frommethanol-Et₂O afforded 2.65 g of 2a•fumarate as a white solid: mp185-186° C. ¹H NMR (CD₃OD) δ 8.36 (s, 1H), 8.13-8.09 (dd, 1H), 7.81 (d,1H), 5.20 (t, 1H), 2.13-2.01 (m, 2H), 1.35 (s, 9H), 0.90 (t, 3H). Anal.(C₁₈H₂₃Cl₂NO₅) C, H, N.

Synthesis of 2-(tert-Butylamino)-3′,4′-dichloropentanophenone (2bb)

Step 1. 3′,4′-Dichloropentanophenone (9bb). To a solution of 4.0 g(0.023 mol) of 8e in 75 mL of dry tetrahydrofuran cooled to 0° C. wasadded dropwise 28 mL (2.0 M in tetrahydrofuran) of butylmagnesiumchloride. The reaction solution was allowed to warm to room temperatureand stirred for 144 h under nitrogen. The reaction solution was cooledto 0° C., and 200 mL of a 5% aqueous hydrochloric acid solution wasadded dropwise. After stirring overnight at room temperature, thereaction mixture was quenched with a saturated aqueous sodiumbicarbonate solution, and the product was extracted with methylenechloride, dried (Na₂SO₄), and filtered. The solvent was removed, and theresulting residue was dried briefly under high vacuum to give 5.71 g ofa brown solid. Purification by flash chromatography (silica, 3:1hexane-methylene chloride) gave 4.30 g (80%) of 9bb as a light brownsolid. ¹H NMR (CDCl₃) δ 8.02 (s, 1H), 7.80-7.76 (dd, 1H), 7.54 (d, 1H),2.92 (t, 2H), 1.77-1.63 (m, 2H), 1.48-1.33 (m, 2H), 0.95 (t, 3H).

Step 2. 2-Bromo-3′,4′-dichloropentanophenone (10bb). To a solution of4.23 g (0.018 mol) of 9bb in 70 mL of methylene chloride was added tendrops of bromine. After stirring at room temperature under nitrogen forseveral minutes, the characteristic red color of bromine disappearedindicating initiation of the reaction. The remainder of the 1 mL (18.30mmol) of bromine was added dropwise, and the reaction solution wasallowed to stir at room temperature under nitrogen for 9.5 h. Thereaction solution was quenched and brought to pH 9 with a saturatedaqueous solution of sodium bicarbonate and concentrated ammoniumhydroxide. The product was extracted with methylene chloride, dried(Na₂SO₄), and filtered. The solvent was removed, and the resultingresidue was dried briefly under high vacuum to give 5.70 g (100%) of10bb as an orange oil. ¹H NMR (CDCl₃) δ 8.09 (s, 1H), 7.86-7.82 (dd,1H), 7.55 (d, 1H), 5.02 (t, 1H), 2.19-2.10 (m, 2H), 1.60-1.42 (m, 2H),0.99 (t, 3H).

Step 3. 2-(tert-Butylamino)-3′,4′-dichloropentanophenone (2bb) Fumarate.To a pressure tube was transferred 5.56 g (0.018 mol) of 10bb with aminimal amount of methylene chloride. Most of the methylene chloride wasremoved via positive nitrogen flow, 28 mL (269.01 mmol) oftert-butylamine was added in one portion, and the tube was sealed andplaced in an oil bath heated to 70° C. After stirring at 70° C. for 3 h,tert-butylamine began to escape from the reaction tube, and the reactionmixture was allowed to cool to room temperature. The reaction mixturewas quenched and brought to a pH of 10 with a saturated aqueous solutionof sodium bicarbonate, and the product was extracted with methylenechloride, dried (Na₂SO₄), and filtered. The solvent was removed, and theresulting residue was dried briefly under high vacuum to give 5.0 g ofan orange oil which TLC (9:1:20 Et₂O-Et₃N-hexane) showed to be an 80/20mixture of starting material/product. The mixture was submitted to theoriginal reaction conditions for 24 h using 19 mL (179.30 mmol) oftert-butylamine and to the original work-up conditions to give 5.61 g ofan orange oil. Purification by flash chromatography (silica, 9:1:60Et₂O-Et₃N-hexane) gave 2.44 g (45%) of 2bb as an orange oil. ¹H NMR(CDCl₃) δ 8.08 (s, 1H), 7.85-7.80 (dd, 1H), 7.58 (d, 1H), 4.10-4.05 (m,1H), 1.54-1.26 (m, 4H), 1.01 (s, 9H), 0.94-0.88 (m, 3H). To a solutionof 2.27 g (0.0075 mol) of 2bb in methylene chloride-methanol was added0.87 g (0.0075 mol) of fumaric acid. The reaction solution was allowedto stir for 15 min, and the solvent was removed in vacuo leaving a whitesolid. Recrystallization from methanol-Et₂O afforded 1.86 g of2bb•fumarate as a white solid: mp 177-179° C. ¹H NMR (CD₃OD) δ 8.35 (s,1H), 8.12-8.08 (dd, 1H), 7.81 (d, 1H), 5.17 (t, 1H), 1.96-1.90 (m, 2H),1.34 (bs, 10H), 0.89 (t, 3H). Anal. (C19H₂₅Cl₂NO₅) C, H, N.

a) Synthesis of Compounds for Comparison Synthesis of2-(N-tert-Butylamino)propiophenone (2b)

Step 1. 2-Bromopropiophenone (10b). To a solution of 5 g (0.037 mol) ofpriopiophenone, 9b, in 50 mL of CH₂Cl₂ was added 1.92 mL (37.3 mmol) ofBr₂ over 15 min. The solution was allowed to stir for 15 min. Thereaction mixture was washed with 40 mL of saturated NaHCO₃, 40 mL of 1 NNa₂S₂O₃, 40 mL of brine, dried (Na₂SO₄), and concentrated to afford 7.9g (90%) of 10b as a pale yellow oil. ¹H NMR (CDCl₃) δ 8.08-8.02 (d, 2H),7.63-7.58 (t, 1H), 7.56-7.47 (t, 2H), 5.40-5.24 (q, 1H), 1.97-1.90 (d,3H).

Step 2. 2-(N-tert-Butylamino)propiophenone (2b) Fumarate. In a 100 mLround-bottom flask was dissolved 6.27 g (0.027 mol) of 10b in 42.2 mL(402 mmol) of tert-butylamine. The flask was sealed with a rubber septumand stirred for 2 h. The reaction mixture was concentrated in vacuo, theresidue was taken up in 50 mL of 2 N HCl, and 50 mL of Et₂O was added.The acidic layer was collected, basified to pH 11 with 5 N NaOH andextracted with 3×25 mL of CH₂Cl₂. The combined organic layers werewashed with 50 mL of brine, dried (Na₂SO₄), and filtered. The solventwas removed to afford 3.32 g (43%) of 2b as a pale yellow oil. Thefumarate salt was prepared by adding one equivalent of fumaric acid toan Et₂O solution of 2b. Recrystallization of the salt from CH₃OH-Et₂Oafforded a white crystalline solid; mp 183-185° C. ¹H NMR (CDCl₃) δ8.07-8.02 (d, 2H), 7.61-7.57 (t, 2H), 7.55-7.48 (t, 2H), 4.45-4.34 (q,1H), 1.32-1.30 (d, 3H), 1.16-1.04 (s, 9H). Anal. (C₁₇H₂₃NO₅) C, H, N.

Synthesis of 2-(tert-Butylamino)-3′-fluoropropiophenone (2c)

Step 1. 2-Bromo-3′-fluoropropiophenone (10c). To a solution of 2.28 g(0.015 mol) of 3-fluoropropiophenone, 9c, in 60 mL of CH₂Cl₂ was addedten drops of bromine After stirring at room temperature under nitrogenfor several min, the characteristic red color of bromine disappeared,indicating initiation of the reaction. The remainder of the 0.7 mL (15mmol) of bromine was added drop-wise, and the reaction solution wasallowed to stir at room temperature under nitrogen for 11 h. Thereaction solution was quenched and brought to a pH of 9 with a saturatedsodium bicarbonate solution. The product was extracted with methylenechloride, dried (Na₂SO₄), and filtered. The solvent was removed, and theresulting residue was dried briefly under high vacuum to give 3.39 g ofa clear oil. Purification by flash chromatography (silica, 5:1hexane-methylene chloride) gave 2.87 g (83%) of 10c as a clear oil. ¹HNMR (CDCl₃) δ 7.82-7.73 (dd, 1H), 7.69 (d, 1H), 7.52-7.43 (m, 1H),7.33-7.29 (m, 1H), 5.30-5.18 (q, 1H), 1.91 (d, 3H).

Step 2. 2-(tert-Butylamino)-3′-fluoropropiophenone (2c) Fumarate. To asealable reaction tube was transferred 2.87 g (0.019 mol) of 10c with aminimal amount of methylene chloride. Most of the methylene chloride wasremoved via positive nitrogen flow, 13 mL (124.20 mmol) oftert-butylamine was added in one portion, and the tube was sealed andplaced in an oil bath heated to 55° C. After stirring at 55° C. for 17h, the reaction mixture was allowed to cool to room temperature, wasquenched, and was brought to pH 10 with a saturated sodium bicarbonatesolution. The product was extracted with methylene chloride, dried(Na₂SO₄), and filtered. The solvent was removed, and the resultingresidue was dried briefly under high vacuum to give 2.74 g of a paleyellow oil. Purification by flash chromatography (silica, 9:1:50Et₂O-Et₃N-hexane) gave 1.94 g (70%) of 2c as a clear oil. ¹H NMR (CDCl₃)δ 7.80-7.77 (dd, 1H), 7.69 (d, 1H), 7.53-7.44 (m, 1H), 7.32-7.29 (m,1H), 4.35-4.26 (q, 1H), 1.27 (d, 3H), 1.05 (s, 9H). To a solution of1.94 g (0.0087 mol) of 2c in methanol was added 1.00 g (0.0087 mol) offumaric acid. The reaction solution was allowed to stir for 15 min, andthe solvent was removed in vacuo leaving a white solid.Recrystallization from methanol/Et₂O afforded 2.52 g of 2c•fumarate as awhite solid: mp 173-175° C. ¹H NMR (CD₃OD) δ 8.04-8.00 (dd, 1H),7.94-7.89 (dd, 1H), 7.69-7.62 (m, 1H), 7.56-7.52 (m, 1H), 5.27-5.18 (q,1H), 1.59 (d, 3H), 1.36 (s, 9H). Anal. (C₁₇H₂₂FNO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′-bromopropiophenone (2d)

Step 1. 2-Bromo-3′-bromopropiophenone (10d). 3′-Bromopropiophenone 9d(8.0 g, 0.038 mol) was dissolved in 30 mL of methanol at roomtemperature in a 250 mL flask equipped with a magnetic stir bar. Bromine(9.05 g, 0.057 mol) was added over a period of 10 min. Twenty drops of48% hydrobromic acid were added, and the reaction mixture was stirredunder N₂. After 72 h, the solvent and excess reagents were removed underreduced pressure to give 11.66 g of an oil. The dark orange oil waspurified by flash chromatography (4:1 hexane-methylene chloride) toafford 6.99 g (64%) of 10d as a pale yellow oil. ¹H NMR (CD₃OD) δ 8.16(s, 1H), 8.05-7.98 (d, 1H), 7.80-7.75 (d, 1H), 7.47-7.40 (t, 1H),5.60-5.50 (q, 1H), 1.87-1.83 (d, 3H).

Step 2. 2-(N-tert-Butylamino)-3′-bromopropiophenone (2d) Fumarate.Intermediate 10d (6.99 g, 0.0024 mol) and tert-butylamine (25.2 mL, 240mmol) were placed in a pressure tube equipped with a magnetic stir bar.The tube was sealed and heated at 80° C. with an oil bath. After 2 h,the mixture was transferred to a separatory funnel, saturated sodiumbicarbonate solution was added, and the aqueous layer was extracted withmethylene chloride. The organic layer was dried (Na₂SO₄) and filtered.The solvent was removed under reduced pressure. The resulting oil wasdissolved in methanol, and the solvent was removed under reducedpressure to afford 6.42 g (94%) of 2d as a pale yellow oil. ¹H NMR(CD₃OD) δ 8.20 (s, 1H), 8.10-8.05 (d, 1H), 7.83-7.78 (d, 1H), 7.50-7.45(t, 1H), 4.55-4.45 (q, 1H), 1.28-1.23 (d, 3H), 1.06 (s, 9H). Amine 2dwas converted to a fumarate salt using the procedure described for 2b.Recrystallization of the salt from methanol and Et₂O afforded 1.75 g of2d•fumarate as white crystals: mp 174° C. (dec). ¹H NMR (CD₃OD) δ 8.32(s, 1H), 8.18-8.14 (d, 1H), 7.95-7.90 (d, 1H), 7.59-7.51 (t, 1H), 6.69(s, 2H), 5.28-5.19 (q, 1H), 1.60-1.56 (d, 3H), 1.36 (s, 9H). Anal.(C₁₇H₂₂BrNO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′-methylpropiophenone

Step 1. 3′-Methylpropiophenone (9e). 3-Methylbenzonitrile 8a (3.25 g,0.028 mol) and dry THF (75 mL) were placed in a 250 mL flask equippedwith a magnetic stir bar. The flask was cooled to 0° C. using anice-water bath. Ethyl magnesium bromide (33.3 mL, 1 M in THF) was addeddropwise over 10 min. The solution was stirred for 30 min and warmed toroom temperature. After stirring under N₂ for 72 h, 30 mL of crushed icewas added. The mixture was transferred to a separatory funnel, and theaqueous layer was extracted with Et₂O. The organic layer was dried(Na₂SO₄) and filtered. The solvent was removed under reduced pressure toafford 3.86 g (94%) of 9e as a clear oil. ¹H NMR (CDCl₃) δ 7.78-7.71 (m,2H), 7.50-7.32 (m, 2H), 2.40 (s, 3H), 3.05-2.95 (q, 2H), 1.25-1.19 (t,3H).

Step 2. 2-Bromo-3′-methylpropiophenone (10e). Ketone 9e (3.5 g, 0.024mol) and methylene chloride (200 mL) were placed in a 500-mL flaskequipped with a magnetic stir bar. The solution was stirred under N₂ andbromine (1.21 mL, 23.6 mmol) was syringed into flask. (Note: a smallamount of bromine was added to initiate the reaction; the colordissipated as reaction occurs; after reaction mixture was initiated, theremaining bromine was added over 10 min). A needle was placed in thesepta to allow the hydrogen bromide gas formed in the reaction mixtureto escape from the flask. After stirring for 10 h, the solution wastransferred to a separatory funnel. Saturated sodium bicarbonatesolution was added to basify the reaction. The mixture was filered, andthe aqueous layer was extracted with methylene chloride. The organiclayer was dried (Na₂SO₄) and filtered. The solvent was removed underreduced pressure to give 5.38 g of an oil. The dark orange oil waspurified by flash chromatography on silica gel (3:1 hexane-methylenechloride) to afford 3.14 g (59%) of 10e as a pale yellow oil. ¹H NMR(CDCl₃) δ 7.86-7.79 (m, 2H), 7.42-7.32 (m, 2H), 5.35-5.25 (q, 1H), 2.42(s, 3H), 1.93-1.89 (d, 3H).

Step 3. 2-(N-tert-Butylamino)-3′-methylpropiophenone (2e) Fumarate.Compound 10e (3.0 g, 0.013 mol) and tert-butylamine (13.88 mL, 130 mmol)were placed in a pressure tube equipped with a magnetic stir bar. Thetube was sealed and heated at 70° C. with an oil bath. After 2 h, themixture was transferred to a separatory funnel. Water (50 mL) andammonium hydroxide (5 drops) were added, and the aqueous layer wasextracted with methylene chloride. The organic layer was dried (Na₂SO₄)and filtered. The solvent was removed under reduced pressure. The oilwas dissolved in methanol, and the methanol was removed under reducedpressure to afford 2.83 g (98%) of 12e as a pale yellow oil. ¹H NMR(CDCl₃) δ 7.81-7.76 (m, 2H), 7.41-7.35 (m, 2H), 4.40-4.30 (q, 1H), 2.44(s, 3H), 1.29-1.23 (d, 3H), 1.05 (s, 9H). Amine 2e was converted to afumarate salt using the procedure described for 2b. Recrystallization ofthe salt from methanol and Et₂O afforded 3.43 g of 2e•fumarate as whitecrystals: mp 172-174° C. (dec). ¹H NMR (CD₃OD) δ 8.00-7.93 (m, 2H),7.61-7.57 (d, 1H), 7.53-7.46 (t, 1H), 6.68 (s, 2H), 5.29-5.19 (q, 1H),2.46 (s, 3H), 1.60-1.55 (d, 3H), 1.36 (s, 9H). Anal. (C₁₈H₂₅NO₅.0.25H₂O)C, H, N.

Synthesis of 2-(N-tert-Butylamino)-4′-chloropropiophenone

Step 1. 2-Bromo-4′-chloropropiophenone (10f). 4′-Chloropropiophenone 9f(4.58 g, 0.027 mol) was dissolved in 30 mL of methanol at roomtemperature in a 250 mL flask equipped with a magnetic stir bar. Bromine(1.67 mL, 32.6 mmol) was added over a period of 10 min. Seven drops of48% hydrobromic acid were added, and the reaction mixture was stirredunder N₂. After 110 h, the solution was transferred to a separatoryfunnel, saturated sodium bicarbonate solution was added, and the aqueouslayer was extracted with methylene chloride. The organic layer was dried(Na₂SO₄) and filtered. The solvent was removed under reduced pressure togive 6.60 g (98%) of 10f as an orange oil. ¹H NMR (CDCl₃) δ 8.00-7.94(d, 2H), 7.50-7.44 (d, 2H), 5.27-5.19 (q, 1H), 1.92-1.89 (d, 3H).

Step 2. 2-(N-tert-Butylamino)-4′-chloropropiophenone (2f) Fumarate.Intermediate 10f (6.60 g, 0.027 mol) and tert-butylamine (28.02 mL, 267mmol) were placed in a pressure tube equipped with a magnetic stir bar.The tube was sealed and heated at 75° C. with an oil bath. After 1.5 h,the mixture was transferred to a separatory funnel, saturated sodiumbicarbonate solution was added, and the aqueous layer was extracted withmethylene chloride. The organic layer was dried (Na₂SO₄) and filtered.The solvent was removed under reduced pressure. The oil was dissolved inmethanol and the solvent was removed under reduced pressure to afford6.21 g (97%) of 2f as a light yellow oil. ¹H NMR (CD₃OD) δ 8.10-8.04 (d,2H), 7.59-7.53 (d, 2H), 4.55-4.46 (q, 1H), 1.27-1.25 (d, 3H), 1.06 (s,9H). Amine 2f was converted to a fumarate salt using the proceduredescribed for 2b. Recrystallization of the salt from methanol afforded3.92 g of 2f•fumate as white crystals: mp 197° C. (dec). ¹H NMR (CD₃OD)δ 8.18-8.13 (d, 2H), 7.67-7.62 (d, 2H), 5.25-5.16 (q, 1H), 1.60-1.56 (d,3H), 1.36 (s, 9H). Anal. (C₁₇H₂₂ClNO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-4′-bromopropiophenone (2g)

Step 1. 2-Bromo-4′-bromopropiophenone (10g). A flask was charged with4′-Bromopropiophenone (5.0 g, 0.023 mol) and 25 ml of dichloromethaneand 1M ethereal HCl (0.25 mL, 0.00025 mol). A solution of bromine (7.6ml, 0.148 mol total including the drop added earlier) anddichloromethane (25 ml) was added. A small amount of bromine was addedinitially to catalyze the reaction. After the reaction started, theremaining bromine was added over a 30 min period. After stirring for 18h, the reaction mixture was poured into a saturated solution of sodiumbicarbonate (50 ml) and solid sodium bicarbonate added until slightlyalkaline. The layers were separated and the organic layer was washedwith brine (50 ml), dried over sodium sulfate, and concentrated to give35.1 g (96%) of 10 g of yellow oil. ¹H NMR (CDCl₃) δ 7.91-7.86 (d, 2H),7.65-7.60 (d, 2H), 5.26-5.19 (q, 1H), 1.92-1.89 (d, 3H).

Step 2. 2-(N-tert-Butylamino)-4′-bromopropiophenone (2g) Fumarate.Intermediate 10g (8.04 g, 0.028 mol) and tert-butylamine (28.9 mL, 275mmol) were placed in a pressure tube equipped with a magnetic stir bar.The tube was sealed and heated at 80° C. with an oil bath. After 2 h,the mixture was transferred to a separatory funnel, saturated sodiumbicarbonate solution was added, and the aqueous layer was extracted withmethylene chloride. The organic layer was dried (Na₂SO₄) and filtered.The solvent was removed under reduced pressure. The oil was dissolved inmethanol and the solvent was removed under reduced pressure to afford7.53 g (96%) of 2g as a yellow oil. ¹H NMR (CD₃OD) δ 8.01-7.96 (d, 2H),7.75-7.70 (d, 2H), 4.54-4.45 (q, 1H), 1.25-1.21 (d, 3H), 1.06 (s, 9H).Amine 2g was converted to a fumarate salt using the procedure describedfor 2b. Recrystallization of the salt from methanol afforded 6.05 g of2g•fumarate as white crystals: mp 206° C. (dec). ¹H NMR (CD₃OD) δ8.10-8.05 (d, 2H), 7.84-7.78 (d, 2H), 6.69 (s, 2H), 5.24-5.15 (q, 1H),1.59-1.56 (d, 3H), 1.35 (s, 9H). Anal. (C₁₇H₂₂BrNO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-4′-methylpropiophenone (2h)

Step 1. 2-Bromo-4′-methylpropiophenone (10h). 4′-Methylpropiophenone 9h(4.0 g, 0.027 mol) and methylene chloride (100 mL) were placed in a250-mL flask equipped with a magnetic stir bar. The solution was stirredunder N₂ and bromine (1.38 mL, 27.0 mmol) was syringed into flask.(Note: a small amount of bromine was added to initiate the reaction; thecolor dissipated as the reaction occurs; after the reaction initiated,the remaining bromine was added over 10 min.). A needle was placed inthe septa to allow the hydrogen bromide gas formed in the reaction toescape from the flask. After stirring for 10 h, saturated sodiumbicarbonate solution was added to basify the reaction. When the pH was9, the aqueous layer was extracted with methylene chloride. The organiclayer was dried (Na₂SO₄) and filtered. The solvent was removed underreduced pressure to give 6.33 g of 10 h as a white solid. ¹H NMR (CDCl₃)δ 7.94-7.89 (d, 2H), 7.30-7.25 (d, 2H), 5.33-5.23 (q, 1H), 2.42 (s, 3H),1.91-1.87 (d, 3H).

Step 2. 2-(N-tert-Butylamino)-4′-methylpropiophenone (2h) Fumarate.Compound 10h (6.0 g, 0.026 mol) and tert-butylamine (27.76 mL, 260 mmol)were placed in a pressure tube equipped with a magnetic stir bar. Thetube was sealed and heated at 80° C. with an oil bath. After 2 h, themixture was transferred to a separatory funnel. Saturated sodiumbicarbonate solution was added, and the aqueous layer was extracted withmethylene chloride. The organic layer was dried (Na₂SO₄) and filtered.The solvent was removed under reduced pressure. The oil was dissolved inmethanol and the solvent was removed under reduced pressure to afford5.60 g (97%) of 2h as a light orange oil. ¹H NMR (CDCl₃) δ 7.94-7.89 (d,2H), 7.32-7.28 (d, 2H), 4.40-4.30 (q, 1H), 2.42 (s, 3H), 1.29-1.25 (d,3H), 1.05 (s, 9H). Amine 2h was converted to a fumarate salt using theprocedures] described for 2b. Recrystallization of the salt frommethanol and Et₂O afforded 4.50 g of 2h•fumarate as white crystals: mp193-195° C. (dec). ¹H NMR (CD₃OD) δ 8.08-8.04 (d, 2H), 7.45-7.41 (d,2H), 6.68 (s, 2H), 5.24-5.16 (q, 1H), 2.46 (s, 3H), 1.58-1.55 (d, 3H),1.35 (s, 9H). Anal. (C₁₈H₂₅NO₅) C, H, N.

Synthesis of 2-tert-Butylamino-3′,4′-difluoropropiophenone (2i)

Step 1. 2-Bromo-3′,4′-difluoropropiophenone (10i). To a solution of 2 g(0.012 mol) of 3,4-difluoropropiophenone, 9i, in 20 mL of methanol underN₂ was added drop-wise 0.73 mL (14.2 mmol) of bromine A few drops of 48%hydrobromic acid were added to initiate the reaction, and the reactionmixture was allowed to stir at room temperature for 117 h. The reactionmixture was quenched with a saturated sodium bicarbonate solution. Theproduct was extracted with ethyl acetate, dried (Na₂SO₄), and filtered.The solvent was removed, and the resulting residue was dried briefly ona high vacuum pump to afford 2.97 g (101%) of 10i as a clear oil. ¹H NMR(CDCl₃) δ 7.92-7.79 (m, 2H), 7.38-7.13 (m, 1H), 5.22-5.14 (q, 1H), 1.90(d, 3H).

Step 2. 2-tert-Butylamino-3′,4′-difluoropropiophenone (2i) Fumarate. Toa sealable reaction tube was transferred 2.31 g (0.0093 mol) of 10i witha minimal amount of methylene chloride. To the solution was added 9.7 mL(92.70 mmol) of tert-butylamine, the tube was sealed and heated to 75°C. in an oil bath. After stirring for 3 h, the reaction mixture wasquenched with a saturated sodium bicarbonate solution, and the productwas extracted with methylene chloride, dried (Na₂SO₄), and filtered. Thesolvent was removed, and the resulting residue was dried briefly on ahigh vacuum pump to give 2.25 g (100%) of 2i as a yellow oil.Purification by flash chromatography (silica, 9:1:20 Et₂O-Et₃N-hexane)afforded 1.42 g (52%) of 21 as a yellow solid. ¹H NMR (CDCl₃) δ7.90-7.79 (m, 2H), 7.31-7.30 (m, 1H), 4.28-4.26 (q, 1H), 1.27 (d, 3H),1.04 (s, 9H). To a solution of 1.35 g (0.006 mol) of 2i in methanol wasadded 649 mg (5.59 mmol) of fumaric acid. The reaction solution wasallowed to stir at room temperature for 30 min, and the solvent wasremoved in vacuo leaving an off-white solid which was recrystallizedfrom methanol and Et₂O to afford 1.29 g of 2i•fumarate as whitecrystals: mp 185° C. ¹H NMR (CD₃OD) δ 8.18-8.05 (m, 2H), 7.60-7.49 (m,1H), 5.24-5.15 (q, 1H), 1.58 (d, 3H), 1.35 (s, 9H). Anal. (C₁₇H₂₁F₂NO₅)C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′,4′-dichloropropiophenone (2j)

Step 2. 2-Bromo-3′,4′-dichloropropiophenone (10j).3′,4′-Dichloropropiophenone 9j (3.94 g, 0.019 mol) was dissolved in 30mL of methanol at room temperature in a 250 mL flask equipped with amagnetic stir bar. Bromine (1.19 mL, 23.0 mmol) was added over a periodof 10 min Seven drops of 48% hydrobromic acid was added, and thereaction mixture was stirred under N₂. After 110 h, the solution wastransferred to a separatory funnel. Saturated sodium bicarbonatesolution was added, and the aqueous layer was extracted with methylenechloride. The organic layer was dried (Na₂SO₄) and filtered. The solventwas removed under reduced pressure to give 5.47 g (100%) of 10j as anorange oil. ¹H NMR (CDCl₃) δ 8.10 (s, 1H), 7.87-7.83 (d, 1H), 7.56-7.52(d, 1H), 5.22-5.14 (q, 1H), 1.92-1.89 (d, 3H).

Step 3. 2-(N-tert-Butylamino)-3′,4′-dichloropropiophenone (2j) Fumarate.Intermediate 10i (5.47 g, 0.019 mol) and tert-butylamine (20.39 mL, 19mmol) were placed in a pressure tube equipped with a magnetic stir bar.The tube was sealed and heated at 75° C. with an oil bath. After 1.5 h,the mixture was transferred to a separatory funnel, saturated sodiumbicarbonate solution was added, and the aqueous layer was extracted withmethylene chloride. The organic layer was dried (Na₂SO₄) and filtered.The solvent was removed under reduced pressure. The oil was dissolved inmethanol, and the solvent was removed under reduced pressure to afford5.10 g (96%) of 2j as a pale yellow oil. ¹H NMR (CD₃OD) δ 8.21 (s, 1H),8.04-8.00 (d, 1H), 7.74-7.70 (d, 1H), 4.54-4.45 (m, 1H), 1.24-1.21 (d,3H), 1.06 (s, 9H). Amine 2j was converted to a fumarate salt using theprocedure described for 2b. Recrystallization of the salt from methanolafforded 1.99 g of 2j•fumarate as white crystals: mp 196-197° C. (dec).¹H NMR (CD₃OD) δ 8.35 (s, 1H), 8.11-8.07 (d, 1H), 7.82-7.78 (d, 1H),6.68 (s, 2H), 5.24-5.15 (q, 1H), 1.58-1.55 (d, 3H), 1.35 (s, 9H). Anal.(C₁₇H₂₂Cl₂NO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-3′-chloro-4′-methylpropiophenone (2k)

Step 1. 3′-Chloro-4′-methylpropiophenone (9k). To a solution of 2.5 g(0.017 mol) of 3-chloro-4-methylbenzonitrile, 8b, in 100 mL of dry THFcooled to 0° C. under N₂ was added 33.0 mL (33.0 mmol) of 1 M EtMgBr/THFvia syringe over 5 min. The reaction mixture was allowed to warm to roomtemperature and was stirred for 72 h. The reaction mixture was cooled to0° C., and 75 mL of 1 N HCl was slowly added. The mixture was stirredfor 1.5 h at 0° C., diluted with 100 mL of H₂O, and extracted with 3×75mL of Et₂O. The combined organic layers were washed with 50 mL ofsaturated NaHCO₃ solution, 50 mL of brine, dried (MgSO₄), and filtered.The solvent was removed to afford 2.96 g (98%) of 9k as a pale yellowsolid. ¹H NMR (CDCl₃) δ 8.21 (s, 1H), 7.87-7.3 (d, 1H), 7.39-7.20 (d,1H), 3.00-2.91 (q, 2H), 2.43 (s, 3H), 1.28-1.13 (t, 3H).

Step 2. 2-Bromo-3′-chloro-4′-methylpropiophenone (10k). To a solution of1.5 g (0.008 mol) of 9k in 40 mL of CH₂Cl₂ was added 1.31 g (0.008 mol)of Br₂ over 15 min. The solution was allowed to stir for 16 h anddiluted with 60 mL of saturated NaHCO₃ solution, and the organic layerwas separated. The aqueous layer was extracted with 2×50 mL of CH₂Cl₂.The combined organic layers were dried (Na₂SO₄) and filtered. Thesolvent was removed to afford an orange oil. Chromatography (200 g SiO₂;petroleum Et₂₀, 1:1 pet. Ether-Et₂O) afforded 1.4 g (65%) of 10k as aslightly off-white solid. ¹H NMR (CDCl₃) δ 8.06-8.00 (s, 1H), 7.88-7.79(d, 1H), 7.43-7.30 (d, 1H), 5.29-5.18 (q, 2H), 2.45 (s, 3H), 1.97-1.88(d, 3H).

Step 3. 2-(N-tert-Butylamino)-3′-chloro-4′-methylpropiophenone (2k)Fumarate. In a 25 mL pressure tube equipped with a stir bar wasdissolved 1.25 g (0.0048 mol) of 10k in 7.53 mL (71.7 mmol) oftert-butylamine. The tube was sealed and heated to 80° C. on an oilbath. After 2.5 h, the reaction mixture was cooled and taken up in 20 mLof Et₂0 and 20 mL of saturated NaHCO₃ solution. The organic layer wasseparated, and the aqueous layer was extracted with 2×10 mL of Et_(z)O.The combined organic layers were washed with 20 mL of saturated NaHCO₃solution, 20 mL of brine, dried (MgSO₄), and filtered. The solvent wasremoved to afford 1.2 g (99%) of slightly impure 2k as a yellow oil. Thefumarate salt was prepared as described for 2b. Recrystallization fromMeOH-EtOAc to afford 1.24 g of 2k•fumarate as a white crystalline solid:mp 196-198° C. ¹H NMR (d₆-DMSO) δ 8.13 (s, 1H), 8.06-8.00 (d, 1H),7.65-7.55 (d, 1H), 6.58 (s, 2H), 4.69-4.58 (q, 2H), 2.51 (s, 2H), 2.42(s, 3H), 1.20-1.17 (d, 3H), 1.04 (s, 9H). Anal. (C₁₈H₂₄ClNO₅) C, H, N.

Synthesis of 2-(N-tert-Butylamino)-4′-bromo-5′-methylpropiophenone (21)

Step 1. 2-Bromo-4′-bromo-5′-methylpropiophenone (101). To a solution of1.5 g (0.0082 mol) of 4-bromo-5-methylpropiophenone, 91, in 40 mL ofCH₂Cl₂ was added 0.32 mL (6.27 mmol) of Br₂ over 15 min. The solutionwas allowed to stir for 15 min. The reaction mixture was washed with3×40 mL of saturated NaHCO₃ solution, 40 mL of brine, dried (Na₂SO₄),and concentrated to afford 1.9 g (99%) of 101 as a pale yellow oil. ¹HNMR (CDCl₃) δ 7.88 (s, 1H), 7.70-7.61 (m, 2H), 5.31-5.20 (q, 2H), 2.47(s, 3H), 1.97-1.82 (d, 3H).

Step 2. 2-(N-tert-Butylamino)-4′-bromo-5′-methylpropiophenone (21)Fumarate. In a 25 mL pressure tube equipped with a stir bar wasdissolved 1.90 g (0.062 mol) of 101 in 9.79 mL (93.2 mmol) oftert-butylamine. The tube was sealed and heated to 60° C. on an oilbath. After 2.5 h, the cooled reaction mixture was poured into 50 mL ofEt₂O washed with 3×50 mL of saturated NaHCO₃ solution, 50 mL of brine,dried (MgSO₄), and filtered. The solvent was removed to afford 1.8 g(97%) of slightly impure 21 as an orange oil. The fumarate salt wasprepared as described for 2b, recrystallized twice from MeOH to afford1.05 g of 2l•fumarate as a white crystalline solid: mp 198-200° C. ¹HNMR (d₆-DMSO) δ 8.09 (s, 1H), 7.88-7.85 (d, 1H), 7.80-7.73 (d, 1H), 6.58(s, 2H), 4.70-4.53 (q, 2H), 250-2.45 (s, 1H), 2.38-2.36 (s, 3H),1.25-1.20 (d, 3H), 1.04 (2, 9H). Anal. (C₁₈H₂₄BrNO₅) C, H, N.

Synthesis of 2-(tert-Butylamino)-3′,5′-difluoropropiophenone (2m)

Step 1. 2-Bromo-3′,5′-difluoropropiophenone (10m). To a solution of 3.00g (0.018 mol) of 3,5-difluoropropiophenone, 9m, in 70 mL of methylenechloride was added 10 drops of bromine. After stirring at roomtemperature under nitrogen for several minutes, the characteristic redcolor of bromine disappeared indicating initiation of the reaction. Theremainder of the 0.9 mL (17.63 mmol) of bromine was added dropwise, andthe reaction solution was allowed to stir at room temperature undernitrogen overnight. The reaction solution was quenched and brought to apH of 9 with a saturated sodium bicarbonate solution. The product wasextracted with methylene chloride, dried (Na₂SO₄), and filtered. Thesolvent was removed, and the resulting residue was dried briefly underhigh vacuum to give 4.36 g (99%) of 10m as a clear oil. ¹H NMR (CDCl₃) δ7.57-7.49 (bdd, 2H), 7.09-7.01 (m, 1H), 5.30-5.10 (q, 1H), 1.91 (d, 3H).

Step 2. 2-(tert-Butylamino)-3′,5′-difluoropropiophenone (2m) Fumarate.To a sealable reaction tube was transferred 4.36 g (0.018 mol) of 10mwith a minimal amount of methylene chloride. Most of the methylenechloride was removed via positive nitrogen flow, 19 mL (175.05 mmol) oftert-butylamine was added in one portion, and the tube was sealed andplaced in an oil bath heated to 80° C. After stirring at 80° C. for 2 h,the reaction mixture was allowed to cool to room temperature, quenched,and brought to a pH of 10 with a saturated sodium bicarbonate solution.The product was extracted with methylene chloride, dried (Na₂SO₄), andfiltered. The solvent was removed, and the resulting residue was driedbriefly under high vacuum to give 4.09 g of an orange oil. Purificationby flash chromatography (silica, 9:1:50 Et₂O-Et₃N-hexane) gave 3.29 g(78%) of 2m as a yellow oil. ¹H NMR (CDCl₃) δ 7.54-7.50 (dd, 2H),7.08-7.01 (m, 1H), 4.27-4.22 (q, 1H), 1.27 (d, 3H), 1.05 (s, 9H). To asolution of 3.22 g (0.013 mmol) of 2m in methanol was added 1.54 g(0.013 mol) of fumaric acid. The reaction solution was allowed to stirfor 15 min, and the solvent was removed in vacuo leaving a white solid.Recrystallization from methanol-Et₂O afforded 4.00 g of 2m•fumarate as awhite solid: mp 170-172° C. ¹H NMR (CD₃OD) δ 7.84-7.81 (dd, 2H),7.46-7.39 (m, 1H), 5.21-5.15 (q, 1H), 1.58 (d, 3H), 1.35 (s, 9H). Anal.(C₁₇H₂₁F₂NO₅) C, H, N.

Synthesis of 2-(tert-Butylamino)-3′,5′-dichloropropiophenone (2n)

Step 1. 3′,5′-Dichloropropiophenone (9n). To a solution of 5.24 g (0.031mol) of 3,5-dichlorobenzonitrile, 8c, in 100 mL of dry tetrahydrofurancooled to 0° C. was added dropwise 35 mL (2.0 M in Et₂O) ofethylmagnesium chloride. The reaction solution was allowed to warm a toroom temperature and stir at room temperature for 74 h under nitrogen.The reaction solution was cooled to 0° C., and 250 mL of a 5% aqueoushydrochloric acid solution was added dropwise. After stirring overnightat room temperature, the reaction mixture was quenched with a saturatedaqueous sodium bicarbonate solution and basified to pH 11 withconcentrated ammonium hydroxide. The product was extracted withmethylene chloride, dried (Na₂SO₄), and filtered. The solvent wasremoved, and the resulting residue was dried briefly under high vacuumto give 6.21 g of a brown solid. Purification by flash chromatography(silica, 5:1 hexane-methylene chloride) gave 4.94 g (80%) of 9n as awhite non-crystalline solid. ¹H NMR (CDCl₃) δ 7.81 (s, 2H), 7.54 (s,1H), 3.00-2.92 (q, 2H), 1.23 (t, 3H).

Step 2. 2-Bromo-3′,5′-dichloropropiophenone (10n). To a solution of 5.59g (0.028 mol) of 9n in 90 mL of methylene chloride was added 10 drops ofbromine. After stirring at room temperature under nitrogen for severalminutes, the characteristic red color of bromine disappeared indicatinginitiation of the reaction. The remainder of the 1.40 mL (27.53 mmol) ofbromine was added dropwise, and the reaction solution was allowed tostir at room temperature under nitrogen for 9.75 h. The reactionsolution was quenched and brought to pH 8 with a saturated aqueoussolution of sodium bicarbonate. The product was extracted with methylenechloride, dried (Na₂SO₄), and filtered. The solvent was removed, and theresulting residue was dried briefly under high vacuum to give 8.73 g(>100%) of 10b as a light yellow oil. ¹H NMR (CDCl₃) δ 7.86 (s, 2H),7.56 (s, 1H), 5.19-5.11 (q, 1H), 1.90 (d, 3H).

Step 3. 2-(tert-Butylamino)-3′,5′-dichloropropiophenone (2n) Fumarate.To a sealable reaction tube was transferred 4.00 g (0.014 mol) of 10nwith a minimal amount of methylene chloride. Most of the methylenechloride was removed via positive nitrogen flow, 15 mL (141.86 mmol) oftert-butylamine was added in one portion, and the tube was sealed andplaced in an oil bath heated to 65° C. After stirring at 65° C. for 2 h,the reaction mixture was allowed to cool to room temperature. Thereaction mixture was quenched and brought to pH 10 with a saturatedaqueous solution of sodium bicarbonate, and the product was extractedwith methylene chloride, dried (Na₂SO₄), and filtered. The solvent wasremoved, and the resulting residue was dried briefly under high vacuumto give 4.20 g of 2n as an orange oil. ¹H NMR (CDCl₃) δ 7.86 (s, 2H),7.58 (s, 1H), 4.27-4.19 (q, 1H), 1.25 (d, 3H), 1.05 (s, 9H).Purification by flash chromatography (silica, 9:1:40 Et₂O-Et₃N-hexane)gave 2.67 g (69%) of 2n as a yellow oil. To a solution of 2.50 g (0.009mol) of 2n in methanol was added 1.05 g (0.009 mol) of fumaric acid. Thereaction mixture was allowed to stir for 15 min, and a white solidprecipitated from the solution which was collected by vacuum filtrationto afford 1.69 g of 2n•fumarate as a white solid: mp 178-180° C. ¹H NMR(CD₃OD) δ 8.14 (s, 2H), 7.96 (s, 1H), 4.67-4.59 (q, 1H), 1.21 (d, 3H),1.05 (s, 9H). Anal (C₁₇H₂₁Cl₂NO₅) C, H, N.

Synthesis of 2-(N-Propylamino)-3′-chloropropiophenone (2v)2-(N-Propylamino)-3′-chloropropiophenone (2v) Fumarate

2-Bromo-1-(3-chlorophenyl)propan-1-one (250 mg, 1.01 mmol) was dissolvedin dry ether (1 mL) and the solution was chilled to 0° C. n-Propylamine(0.18 mL, 2.22 mmol) was then added all at once and the reaction mixturewas allowed to warm to room temperature and stir overnight. The reactionmixture was diluted with water and ether and stirred for 5 min. Thebiphasic mixture was partitioned in a separatory funnel. The aqueouslayer was extracted twice with ether and the combined organic extractswere washed twice with 1 M aqueous HCl. The combined acidic aqueouslayers were then basified to pH 8-9 with saturated aqueous Na₂CO₃. Thebasified aqueous layer was extracted twice with ether and the combinedorganic extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated to approximately half the original volume. (Caution: Inall the following concentration steps, do not concentrate to dryness orthe compound will decompose). In order to remove the unreactedpropylamine, MeOH (˜20 mL) was added and the solution was concentratedto ˜5-10 mL. This process was repeated twice more and then 30 mL ofether was added followed by the dropwise addition of 1 M HCl/ether untilthe solid stopped precipitating out of solution (typically 0.5 to 1 mLwas needed). After stirring for 1 h, the solid was filtered, washed withether, and dried to afford 67.1 mg (25% yield) of the hydrochloride saltof 2v as a white flaky solid: mp 188-189° C. ¹H NMR (CD₃OD, 300 MHz) δ8.07 (s, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.76 (d, J=12.0 Hz, 1H), 7.61 (t,J=12.0, 6.0 Hz, 1H), 5.17 (q, J=21.0, 15.0, 6.0 Hz, 1H), 3.13-3.04 (m,1H), 3.02-2.92 (m, 1H), 1.86-1.73 (m, 2H), 1.58 (d, J=9.0 Hz, 3H), 1.05(t, J=15.0, 9.0 Hz, 3H); ¹³C NMR (CD₃OD, 75 MHz) ppm 196.1, 136.0,135.9, 132.1, 129.7, 128.4, 59.6, 49.0, 20.9, 16.3, 11.2. Anal.(C₁₂H₁₇Cl₂NO.0.25H₂O)C, H, N.

The initial preparation of 2v was of the fumaric salt, using fumaricacid in place of HCl/ether, but it was difficult to repeat and the yieldwas <5%. It was then discovered that the hydrochloride salt resulted inmore reliable isolation. The fumarate salt is reported because that iswhat was used for the biological testing. The fumarate salt was madefrom the hydrochloride salt by neutralization with aqueous sodiumbicarbonate followed by extraction with ether. Fumaric acid was thenadded as a solution in methanol and the solution concentrated until asolid appeared, which was filtered, washed with ether, and dried toafford 2v•fumarate: mp 190-192° C. (dec). Anal. (C₁₆H₂₀ClNO₅.0.25H₂O)C,H, N.

Synthesis of 2-(N-Isopropylamino)-3′-chloropropiophenone (2w) Fumarate.Sodium bicarbonate (4 g, 0.048 mol) was suspended in a solution of 10 g(6.00, 0.024 mol) in acetonitrile (30 mL). The suspension was cooled inan ice-brine bath and a solution of isopropylamine (0.69 g, 0.012 mol)in acetonitrile (10 mL) added dropwise over a period of 10 min. Afterthe addition was complete, the mixture was stirred in the cold for 4 h,poured into a mixture of hydrochloric acid (50 mL of 10%) and ethylacetate (50 mL). The aqueous layer was separated, washed with ethylacetate (25 mL) and made alkaline with ammonia hydroxide:water (1:1).The mixture was extracted with Et₂O (2×100 mL) and the combined etherealextracts were dried (K₂CO₃), filtered, and concentrated to give 1.26 gof yellow oil. The fumarate salt was formed as described for 2b andrecrystallized from methanol/Et₂O: mp 174-178° C. (dec). ¹H NMR (CDCl₃)δ 7.88 (t, 1H, J=1.6 Hz), 7.78 (dd, 1H, J=2.1 Hz, J=1.2 Hz), 7.48 (d,J=2.1 Hz), 7.37 (t, J=7.8 Hz), 4.30 (q, 1H, J=7.2 Hz), 2.67 (p. 1H,J=6.3 Hz), 1.23 (d, 2H, J=15 Hz), 1.00 (t, 6H, J=6.3 Hz). Anal.(C₁₆H₂₀ClNO₅.0.25 H₂O)C, H, N.

Synthesis of 2-(N-Methyl-N-tert-butylamino)-3′-chloropropiophenone (2cc)

Step 1. 2-Bromo-3′-chloropropiophenone (10 cc). 3′-Chloropropiophenone(10.0 g, 0.059 mol) and methylene chloride (100 mL) were placed in a500-mL flask equipped with a magnetic stir bar. The solution was stirredunder nitrogen, and bromine (3.04 mL, 59 mmol) was syringed into theflask. A small amount of bromine was added initially to catalyze thereaction. After reaction started, the remaining bromine was added over a10-min period. The hydrogen bromide gas evolved was bubbled through a0.1 N sodium hydroxide solution. After stirring for 16 h, the solutionwas transferred to a reparatory funnel. A saturated sodium bicarbonatesolution was added to basify the reaction, and the aqueous layer wasextracted three times with methylene chloride. The organic layer wasdried (Na₂SO₄) and filtered. The solvent was removed under reducedpressure to give 14.06 g of oil. The dark orange oil was purified byflash chromatography (4:1 hexane-methylene chloride) to afford 13.90 g(95%) of 10 cc as a light orange oil. ¹H NMR (CDCl₃) δ 7.99 (s, 1H),7.93-7.88 (d, 1H), 7.61-7.56 (d, 1H), 7.49-7.40 (t, 1H), 5.29-5.19 (q,1H), 1.94-1.89 (d, 3H).

Step 2. 2-(N-Methyl-N-tert-butylamino)-3′-chloropropiophenone (2 cc)Hydrochloride.

Compound 10 cc (5.0 g, 0.02 mol) and methylene chloride (50 mL) wereplaced in a pressure tube equipped with a magnetic stir bar.N-Methyl-N-tert-butylamine (4.97 mL, 41 mmol) was added to the tube. Thetube was sealed, stirred, and refluxed at 75° C. for 6 h. The tube wascooled to room temperature and opened. After stirring 8 days, thesolution was transferred to a separatory funnel. A saturated sodiumbicarbonate solution was added to basify the reaction, and the aqueouslayer was extracted three times with methylene chloride. The organiclayer was dried (Na₂SO₄) and filtered through a fitted funnel packedwith alumina. The solvent was removed under reduced pressure to give3.65 g (71%) of 2 cc as a green oil. ¹H NMR (CDCl₃) δ 8.09 (s, 1H),7.94-7.89 (d, 1H), 7.50-7.45 (d, 1H), 7.40-7.32 (t, 1H), 4.66-4.56 (q,1H), 2.16 (s, 3H), 1.30-1.25 (d, 3H), 1.19 (s, 9H). Amine 2 cc wasconverted to a hydrochloride salt using the procedure described for 2b.Recrystallization from isopropanol and Et₂O afforded 2.22 g of 2 cc•HClas a white crystalline solid: mp 181-182° C. ¹H NMR (CD₃OD) δ 8.19 (s,1H), 8.19-8.12 (d, 1H), 7.80-7.75 (d, 1H), 7.67-7.60 (t, 1H), 5.59-5.50(q, 1H), 2.97 (s, 3H), 1.63-1.58 (d, 3H), 1.50 (s, 9H). Anal.(C₁₄H₂₁Cl₂NO)C, H, N.

Synthesis of 2-(N,N-Dimethylamino)-3′-chloropropiophenone (2dd)

Compound 10 cc (2.7 g, 0.011 mol) and methylene chloride (40 mL) wereplaced in a sealed tube equipped with a magnetic stir bar. The tube wascooled to −78° C. with an acetone-dry-ice bath. Dimethyl amine(approximately 5 mL, b.p. −7°) was condensed into the tube. The tube wassealed, placed in an ice water bath, and stirred. After stirring 12 h,the tube was again cooled to −78° with an acetone/dry-ice bath andopened. The tube was allowed to warm to room temperature. After stirringfor 4 h at room temperature, the solution was transferred to aseparatory funnel. Water (75 mL) and ammonium hydroxide (10 drops) wereadded to basify the reaction, and the aqueous layer was extracted threetimes with methylene chloride. The organic layer was dried (Na₂SO₄) andfiltered. The solvent was removed under reduced pressure to give 3.14 g(99%) of oil. ¹H NMR (CDCl₃) δ 8.05 (s, 1H), 7.99-7.93 (d, 1H),7.56-7.50 (d, 1H), 7.44-7.36 (t, 1H), 4.05-3.95 (q, 1H), 2.30 (s, 6H),1.22-1.28 (d, 3H). Amine 2dd was filtered, converted to a fumarate saltusing the procedure described for 2b. Recrystallization from methanoland Et₂O afforded 1.80 g of 2dd•fumarate as a white solid: mp 144-145°C. ¹H NMR (CD₃OD) δ 8.04 (s, 1H), 8.00-7.95 (d, 1H), 7.76-7.71 (d, 1H),7.62-7.55 (t, 1H), 6.69 (s, 2H), 2.92 (s, 6H), 1.58 (s, 3H). (Note: Theα proton exchanged with the deuterated solvent; therefore, ¹H NMRspectrum changes slightly.) Anal. (C₁₅H₁₈ClNO₅) C, H, N.

Synthesis of 2-(N,N-Diethylamino)-3′-chloropropiophenone (2ee) Fumarate

Compound 10 cc (4.3 g, 0.017 mol) was placed in a 250-mL flask equippedwith a magnetic stir bar. The flask was cooled to 0° C. with anice-water bath. Diethylamine (3.77 mL, 36 mmol) was added, and thereaction was stirred under nitrogen. After 12 h, the solution wastransferred to a separatory funnel. A saturated sodium bicarbonatesolution was added to basify the reaction, and the aqueous layer wasextracted three times with Et₂O. The organic layer was dried (Na₂SO₄)and filtered through a fitted funnel packed with alumina. The solventwas removed under reduced pressure to give 3.98 g (95%) of 2ee as alight green oil. ¹H NMR (CDCl₃) δ 8.10 (s, 1H), 8.03-7.98 (d, 1H),7.51-7.46 (d, 1H), 7.40-7.32 (t, 1H), 4.42-4.32 (q, 1H), 2.69-2.42 (m,4H), 1.24-1.19 (d, 3H), 1.07-0.99 (t, 6H). Amine 2ee was converted to afumarate salt using the procedure described for 2b. Recrystallizationfrom isopropanol and hexane afforded 2.46 g of 2ee•fumarate as a whitecrystalline solid: mp 119-120° C. ¹H NMR (CD₃OD) δ 8.11 (s, 1H),8.06-8.01 (d, 1H), 7.76-7.71 (d, 1H), 7.63-7.56 (t, 1H), 6.68 (s, 2H),5.30-5.20 (q, 1H), 3.43-3.28 (m, 2H), 3.24-3.09 (m, 2H), 1.50-1.46 (d,3H), 1.38-1.30 (t, 6H). Anal. (C₁₇H₂₂ClNO₅) C, H, N.

Synthesis of 2-Piperidino-3′-chloropropiophenone (2ff) Fumarate.Compound 10 cc (4.5 g, 0.018 mol) was placed in a 100-mL flask equippedwith a magnetic stir bar. The flask was cooled to 0° C. with anice-water bath. Piperidine (3.78 mL, 38 mmol) was added, and thereaction was stirred under nitrogen. After 12 h, the solution wastransferred to a separatory funnel. A saturated sodium bicarbonatesolution was added to basify the reaction, and the aqueous layer wasextracted three times with Et₂O. Subsequently, more piperidine (4 mL)was added. After stirring for 24 h, the solution was transferred to aseparatory funnel. A saturated sodium bicarbonate solution was added tobasify the reaction, and the aqueous layer was extracted three timeswith methylene chloride. The organic layer was dried (Na₂SO₄) andfiltered through a fritted funnel packed with alumina. The pack waswashed with hexane. The solvent was removed under reduced pressure. Toensure that all of the excess piperidine was removed, methanol andtoluene were added and removed under reduced pressure to give 3.32 g(72%) of 2ff as a light orange oil. ¹H NMR (CDCl₃) δ 8.11 (s, 1H),8.05-8.00 (d, 1H), 7.52-7.47 (d, 1H), 7.42-7.32 (t, 1H), 4.02-3.92 (q,1H), 2.56-2.42 (m, 4H), 1.58-1.47 (m, 4H), 1.47-1.39 (m, 2H), 1.25-1.20(d, 3H). Amine 2ff was converted to a fumarate salt using the proceduredescribed for 2b. Recrystallization from isopropanol and hexane afforded2.84 g of 2ff•fumarate as a white crystalline solid: mp 157-158° C. ¹HNMR (CD₃OD) δ 8.09 (s, 1H), 8.01-7.96 (d, 1H), 7.77-7.71 (d, 1H),7.63-7.53 (t, 1H), 6.70 (s, 3H), 5.22-5.12 (q, 1H), 3.50-3.20 (m, 4H),1.99-1.89 (m, 4H), 1.75-1.65 (m, 2H), 1.60-1.55 (d, 3H). (Note: fumaratepeak, 6.70, integrates for 3 protons. This is supported by the elementalanalysis). Anal. (C₂₀H₂₄ClNO₇) C, H, N.

Synthesis of (1RS,2RS)-2-(N-tert-Butylamino)-1-phenyl-1-propanol (7)Hemifumarate. The title compound was prepared as previously reported(Musso, D. L. et al., Synthesis and Evaluation of the AnticonvulsantActivity of a Series of 2-amino-1-phenyl-1-propanols Derived from theMetabolites of the Antidepressant Bupropion Bioorg. Med. Chem. Lett.1997, 7, 1-6) and characterized as the hemifumarate salt: m.p. 178-180°C. Anal. (C₁₅H₂₃NO₃) C, H, N.

Example 2 Biological Studies a) Monoamine Tranporter Binding and UptakeStudies

The competition binding assays were determined using (h)DAT, (h)SERT,and (h)NET, stably expressed in HEK293 cells, and the non-selectiveradioligand [¹²⁵I]RTI-55 for the analogues 2a-2ff and 7 (See Table 4,below). The HEK-(h)DAT, -(h)SERT, and -(h)NET cells were also used toevaluate the compounds' ability to block the reuptake of [³H]dopamine([³H]DA), [³H]serotonin ([³H]5HT), and [³H]norepinephrine ([³H]NE)(Table 4).

Bupropion analogues with better DAT binding (lower K_(i) values) and[³H]DA uptake (lower IC₅₀ values) were obtained by (a) replacing themethyl group a to the ketone group with medium-size alkyl groups; (b)changing the type and number of substituents on the 3-chlorophenyl ring;and (c) replacing the N-tert-butyl group with other N-alkyl groups.Since for the most part the rank order potency of the binding assaysmirror those of the uptake values, only the monoamine uptake values willbe discussed.

Bupropion has IC₅₀ values of 945 and 443 nM for DA and NE uptakeinhibition, respectively. Since the K_(i) value for binding to the SERTwas >10 μM, the 5HT uptake IC₅₀ was not determined. Thus, bupropion is3.5-times less potent inhibitor of DA uptake than cocaine. Bupropion andcocaine have almost equal potency for NE uptake, and cocaine with anIC₅₀ value of 318 nM for 5HT uptake is much more potent than bupropion.Analogues 2o-2q obtained by replacing the α methyl group in bupropionwith an ethyl, propyl, or butyl group had IC₅₀ values of 31, 33, and 69nM, respectively, compared to 945 nM for bupropion and were the most DAefficacious analogues. Analogues 2s-2t with larger hexyl and isobutyl αsubstituents had IC₅₀ values of 135 and 440 nM and, thus, were alsobetter DA uptake inhibitors than bupropion. Replacement of the α methylgroup in bupropion with a much larger 2-(cyclohexyl)ethyl a substituentto give 2u resulted in complete loss of DA efficacy (IC₅₀ value of >10μM).

Changing the aromatic substituent pattern of bupropion also led toanalogues with better IC₅₀ values for DA uptake inhibition. For example,the 3,4-dichlorophenyl analogue 2j and the 3-chloro, 4-methylphenylanalogue 2k with IC₅₀ values of 271 and 650 nM, respectively, were 3.5-and 2-times more potent than bupropion. The 3-bromophenyl and 4-bromo,3-methylphenyl analogues 2d and 2l with IC₅₀ values of 950 nM were aspotent as bupropion. Replacing the α methyl group of 2j with an ethyl orpropyl group gave analogues 2aa and 2bb, which had slightly lower IC₅₀values than 2j. Replacement of the 3-chlorophenyl ring with a thiophenering led to 3, which had no efficacy for DA uptake inhibition.

Replacement of the N-tert-butyl group with an N-cyclopropyl orN-cyclobutyl group gave 2x and 2y with IC₅₀ values of 265 and 258 nM,which are 3.6- and 3.7-times more potent than bupropion. TheN-cyclopentyl analogue 2z had an IC₅₀ of 980 nM, almost identical tothat of bupropion. The N-isopropyl analogue 2w with an IC₅₀ value of2000 nM was 2-times less potent than bupropion. Surprisingly, theN-propyl analogue 2v was inactive. None of the N,N-disubstitutedanalogues 2cc-2ff had high efficacy for DA uptake inhibition. The bestcompound was the N-piperidino analogue 2ff, which had an IC₅₀ value of1033 nM.

Similar to bupropion, most bupropion analogues showed little efficacyfor 5HT uptake inhibition. The 3-chloro-4-methylphenyl,3-methyl-4-bromopheyl, and N-cyclopentyl analogues 2k, 21, and 2y withIC₅₀ values of 400, 473, and 185 nM for 5HT uptake inhibition,respectively, were the most potent.

Most analogues also showed NE uptake inhibition no better than fivetimes that of bupropion. However, analogues 2bb, 2y, and 2aa with IC₅₀values of 43, 86, and 135, respectively, were 34, 17, and 10 timesbetter as NE uptake inhibitors than bupropion.

Replacement of the cyclopentyl group in 2z with a cyclobutyl orcyclopropyl group to give 2y and 2x, respectively, resulted insignificant changes in monoamine uptake properties. Compound 2z had anIC₅₀ value of 980 nM for DA uptake compared to 258 and 265 nM for 2y and2x, respectively. Surprisingly, the IC₅₀ value for NE uptake for 2z of221 nM improved to 86 nM for the cyclobutyl analogue 2y but increased to2150 nM for the cyclopropyl analogue 2x. The cyclopentyl analogue 2z wastotally inactive as a 5HT uptake inhibitor, whereas the cyclobutylanalogue 2y has an IC₅₀ of 185 nM for this transporter, which is betterthan the other bupropion analogues studied (Table 4). Changing thecyclopentyl in 2z to the cyclopropyl group in 2x also resulted inimproved 5HT uptake inhibition but only to an IC₅₀ value of 3180 nM. Wefound that 2v, which can be viewed as the open ring analogue of 2x, wasinactive at all three transporters. We found that reduction of thecarbonyl of bupropion analogue 2b to give 7 resulted in loss of affinityat the DAT and NET but gave a significant increase in potency for 5HTuptake from >10,000 nM in bupropion to 1240 nM in 7.

TABLE 4 Comparison of Dopamine, Serotonin, and NorepinephrineTransporter Binding and Uptake Studies in C6hDAT, HEK-hSERT, andHEK-hNET Cells for Bupropion Analogues Compounds 2a-2ff

Binding,^(a) K_(i) Uptake,^(a) IC₅₀ (nM) (nM) [³H] [³H]5- [³H] Cmpd R R₁R₂ X Y Z DAT SERT NET DA HT NE co- 272 ± 60  601 ± 130 830 ± 147  267 ± 318 ±  385 ± caine ^(b) 47 57 40 2a CH₃ H C(CH₃)₃ Cl H H 871 ± 126 >10μM 6970 ± 2620  945 ± ^(c)  443 ± (bu- 213 245 pro- pion) 2b CH₃ HC(CH₃)₃ H H H 5730 ± 480  >10 μM 5700 ± 150  2310 ± ^(c) 8700 ± 750 12002c CH₃ H C(CH₃)₃ F H H 4510 ± 460  >10 μM >10 μM 1460 ± ^(c) ^(c) 220 2dCH₃ H C(CH₃)₃ Br H H 4200 ± 1200 >10 μM >7140 ±  950 ± ^(c) 6500 ± 640210 1000 2e CH₃ H C(CH₃)₃ CH₃ H H >10 μM >10 μM >10 μM ^(c) ^(c) ^(c) 2fCH₃ H C(CH₃)₃ H Cl H 2195 ± 151  >10 μM >10 μM 2319 ± ^(c) ^(c) 429 2gCH₃ H C(CH₃)₃ H Br H 1918 ± 221  4170 ± 730  >10 μM 1295 ± 2520 ± ^(c)375 610 2h CH₃ H C(CH₃)₃ H CH₃ H >10 μM >10 μM 6840 ± 1368 ^(c) ^(c)4100 ± 860 2i CH₃ H C(CH₃)₃ F F H >10 μM >10 μM >10 μM ^(c) ^(c) ^(c) 2jCH₃ H C(CH₃)₃ Cl Cl H 472 ± 81  1480 ± 310  5400 ± 1200  271 ± >10 2100± 96 μM 380 2k CH₃ H C(CH₃)₃ Cl CH₃ H 1150 ± 370  2100 ± 510  5100 ±860   650 ±  400 ±  900 ± 150 190 130 2l CH₃ H C(CH₃)₃ CH₃ Br H 1740 ±440  1215 ± 90  4600 ± 601   950 ±  473 ± 1623 ± 310 74 35 2m CH₃ HC(CH₃)₃ F H F 5660 ± 490  >10 μM >10 μM 5600 ± ^(c) ^(c) 1800 2n CH₃ HC(CH₃)₃ Cl H Cl >10 μM >10 μM >10 μM ^(c) ^(c) ^(c) 2o C₂H₅ H C(CH₃)₃ ClH H 459 ± 50  >10 μM 3195 ± 145   31 ± ^(c)  969 ± 9 410 2p C₃H₇ HC(CH₃)₃ Cl H H 96 ± 20 >10 μM 1171 ± 260   33 ± ^(c)  472 ± 7 93 2q C₄H₉H C(CH₃)₃ Cl H H 350 ± 100 >10 μM 3190 ± 850  69 ± ^(c)  400 ± 23 190 2rC₅H₁₁ H C(CH₃)₃ Cl H H  709 ± 8.0  >10 μM 4300 ± 1300 1570 ± ^(c) 2000 ±570 1000 2s C₆H₁₃ H C(CH₃)₃ Cl H H 510 ± 120 >10 μM 2580 ± 700   135 ±^(c) 4890 ± 80 580 2t (CH₃)₂CHCH₂ H C(CH₃)₃ Cl H H 140 ± 14  6200 ± 18002300 ± 700   440 ± >10  360 ± 180 μM 190 2u (C₆H₁₁)CH₂CH₂ H C(CH₃)₃ Cl HH 1700 ± 780  6200 ± 1500 3800 ± 1700 >10 >10 >10 μM μM μM 2v CH₃ HCH₂CH₂CH₃ Cl H H >10 μM >10 μM >10 μM ^(c) ^(c) ^(c) 2w CH₃ H CH(CH₃)₂Cl H H 3980 ± 230  >10 μM >10 μM 2000 ± ^(c) ^(c) 516 2x CH₃ HCH(CH₂CH₂) Cl H H 1150 ± 370  3420 ± 260  4000 ± 1200  265 ± 3180 ± 2150± 94 170 850 2y CH₃ H CH(CH₂CH₂CH₂) Cl H H 343 ± 72  3450 ± 610  1800 ±110   258 ±  185 ±  86 ± 46 49 32 2z CH₃ H CH(CH₂CH₂CH₂CH₂) Cl H H 2200± 490  >10 μM 5700 ± 400   980 ± ^(c)  221 ± 340 94 2aa C₂H₅ H C(CH₃)₃Cl Cl H 278 ± 43  860 ± 230 2240 ± 510   175 ±  790 ±  135 ± 55 320 4.92bb C₃H₇ H C(CH₃)₃ Cl Cl H 43.7 ± 6.5  842 ± 50  520 ± 100  84 ± 1580 ± 43 ± 28 560 14 2cc CH₃ CH₃ C(CH₃)₃ Cl H H 6400 ± 1200 >10 μM >10 μM2060 ± ^(c) ^(c) 340 2dd CH₃ CH₃ CH₃ Cl H H 4133 ± 548  >10 μM 3090 ±740  1534 ± ^(c) 1260 ± 222 290 2ee CH₃ CH₂CH₃ CH₂CH₃ Cl H H 2214 ±308  >10 μM 4476 ± 107  1744 ± ^(c) 4603 ± 288 986 2ff CH₃CH₂CH₂CH₂CH₂CH₂ Cl H H 1148 ± 298  5479 ± 824  4760 ± 1540 1033 ±  970 ±4798 ± 287 178 947 ^(a)Values for the mean ± standard error of threeindependent experiments, each conducted with triplicate determination^(b) Data taken from Musso et al., Synthesis and Evaluation of theAnticonvulsant Activity of a Series of 2-amino-1-phenyl-1-propanolsDerived from the Metabolites of the Antidepressant Bupropion. Bioorg.Med. Chem. Lett. 1997, 7, (1), 1-6 ^(c) Not determined

In addition, 2x is a substrate for the serotonin transporter with anEC₅₀ of 283 nM, which could enhance efficacy at the 5HT (See Table 5,below). The improved efficacy at DA and 5HT combined with weakerefficacy at NE suggests that 2x may be a better pharmacotherapy fortreating cocaine, methamphetamine, and nicotine addiction thanbupropion. Indeed 2x proved to be superior to bupropion in all testedanimal assays, which are presented below.

TABLE 5 Comparison of the 5-HT Releasing/Substrate Activity of a seriesof N- Cyclopropylbupropion analogs using rat brain synaptosomes 5HTRelease Structure (EC50, nM)

(Compound 2x) 283 ± 32 

383 ± 56 

890 ± 63 

676 ± 197

2704 ± 314 

707 ± 69 

148 ± 35 

139 ± 130

b) Locomotor Activity Studies

The bupropion analogues were evaluated for locomotor activity using micein first a 1-h study followed by an 8-h time course study usingpreviously reported methods. The results were compared to the locomotoractivity results obtained for cocaine in both studies and to bupropionin the 8-h study. Cocaine had IC₅₀ values of 8.5-11 mg/kg as determinedin several separate experiments in the 1-h study. The ED₅₀ value forbupropion was 6.5 mg/kg. Cocaine's locomotor efficacy was set at 100%,and all analogues were compared to cocaine's maximum efficacy. ED₅₀values in mg/kg, compounds' maximal effect as a percent of cocaine'smaximal effect in the first 30 min (1-h study), compounds' maximaleffect as a percent of cocaine's maximal effect calculated based on a30-min time period in which maximum stimulation occurred (8-h study),and time period of maximum effect are listed in Table 6, below.

In the 1-h observation protocol, seven analogues had IC₅₀ values similarto cocaine (IC₅₀=5.2-12.1 mg/kg). The IC₅₀ values for 14 compoundsranged from 13.5 to 54.6 mg/kg, and thirteen analogues did not showlocomotor activity. Seven analogues showed stimulation similar tococaine (>84% peak). The remaining 20 compounds with locomotoractivities had peak effects of 41-81% of that of cocaine. In the 8-hlocomotor observation protocol, 7 compounds listed as well as bupropionhad locomotor efficacy similar to cocaine (>84% peak). The remaining 16analogues listed had efficacy ranging from 31-78%. The ED₅₀ valuesranged from 4.4 mg/kg for 2 h to 60.8 mg/kg for 2k. Five analogues, 2b,2c, 2m, 2x, and 2z, had locomotor activity in both the 1-h and 8-htests, and seven analogues, 2d, 2h, 2r, 2s, 2t, 2aa, and 2 cc, were weakstimulants in both tests. Four analogues, 2o, 2p, 2w, and 2dd, showedactivity similar to cocaine in the 1-h protocol but weakenedsignificantly in the 8-h time-course study. Five analogues, 2b, 2c, 2m,2x, and 2z, were strong stimulants in both studies. Four compounds, 2k,2aa, 2bb, and 2ee, showed moderate activity in the 1-h test withincreased activity in the time-course study. Compounds 2g, 2u, 2ff, and6 were inactive in the 1-h test but showed weak stimulant activity inthe 8-h protocol. Several compounds, 2g, 2j, 2p, 2s, 2t, 2dd, 2ff, and6, had periods of maximum stimulatory effects at times of 1 h orgreater. Bupropion's period of maximum stimulatory effect was 0-30 min,which was similar to that of cocaine and analogues 2b-d, 2m, 2o, 2q, and2x-2bb. Compounds 2j, 2t, and 2ff, with a range of 260-350 min timeperiods of maximum effects, had very slow onset of stimulatory activity.Compounds 2j, 2p, 2t, 2ff, and 6 also had duration of locomotor activitygreater than 3 h. Bupropion had a duration of locomotor activity ofapproximately 2-4.5 h. Analogues 2o-q, which were 31-, 29-, and 14-timesmore potent than bupropion as DA uptake inhibitors had very longdurations of locomotor activity of 360, 210-480, and 40-460 min,respectively. In addition, analogue 2x, which was 3.6-times more potentthan bupropion as a DA uptake inhibitor with increased potency as a 5HTuptake inhibitor, possessed a duration of locomotor activity of 350 min,which is longer than bupropion. Analogue 2o also had a much slower onsetof locomotor activity. The cyclopentylbupropion analogue 2z had an ED₅₀value of 10.6 with long durations of action.

TABLE 6 Comparison of Locomotor Activity for Bupropion Analogues at the1- and 8-Hour Observation Protocols Locomotor Activity 8-Hour Time,^(d)Time, 1-Hour % min min ED₅₀ ^(a) % Peak^(b) ED₅₀ ^(a) Peak^(c) Period,Period, Cmpd mg/kg Cocaine mg/kg Cocaine max length cocaine 8.5-11^(e)100 100  0-30  40-100 2a 6.5 87  0-30 130-270 bupropion 2b 8.1 120 10.598  0-30 2c 16.1 84 16.6 90  0-30 150 2d 10.6 72 12.9 57  0-30 120 2e 3176 2f NE^(f) 180-210 2g NE^(f) 32.0 54 140-170 160 2h 8.77 65 4.4 5230-60  60-140 2i 54.6 58 NE 2j NE^(f) 39.1 61 270-300 140-240 2k 31.9 7460.8 87 10-40  60 2l NE^(f) 12.8 46 50-80 240 2m 39.7 93 33.7 95  0-30280 2n NE^(f) 2o 12.1 88 19.3 62  0-30 360 2p 17.2 96 16.3 72  90-120210-480 2q 13.5 81 13.1 110  0-30  40-460 2r 5.82 66 13.4 78 60-90280-460 2s 33.3 61 9.0 60 110-140 130-140 2t 47.7 62 22.1 35 260-290 3202u NE^(f) 15.3 47 60-90  60-160 2v NE^(f) NE^(f) 2w 22.7 84 7.4 65 20-50 50-160 2x 14.7 94 14.7 94  0-30 350 2z 10.6 110 10.6 110  0-30 330-3402aa 50.3 41 42.2 84  0-30  60 2bb 18.1 49 35.0 100  0-30 470 2cc 14.9 7811.2 67  80-110 200-340 2dd 11.0 100 13.9 52  90-120 180-190 2ee 16.6 5520.0 90 20-50 130-240 2ff NE^(f) 15.0 45 320-350 470 ^(a)Dose to produce50% of the compound's maximal effect. ^(b)Compound's maximal effects asa percent of cocaine's maximal effects in the first 30 min.^(c)Compound's maximal effect as a percent of cocaine's maximal effectcalculated based on 30 min time period in which maximum stimulationoccurred. ^(d)Time period of maximum effect. ^(e)Range of ED₅₀ forseveral experiments. ^(f)No locomotor activity or depressant effect.

c) Cocaine Discrimination

The compounds were evaluated for generalization with the cocaine cue bylever choice using standard 2-lever operant chambers in adrug-discrimination task in rats using i.p. administration. Table 7shows the percent of rats choosing the cocaine lever at various doses ofcompounds along with ED₅₀ values where lever choice reached 75%.Analogues were also evaluated for generalization of cocaine using atime-course study with oral administration (Table 8, below) aspreviously reported (Carroll, F. I. et al., Effects of DopamineTransporter Selective 3-Phenyltropane Analogs on Locomotor Activity,Drug Discrimination, and Cocaine Self-administration after OralAdministration. Eur. J Pharmacol. 2006, 553, (1-3), 149-156). Compoundswere dosed p.o. in a volume of 1 mL/kg at 45, 90, 180, or 360 min beforethe session. Results for a compound were again tabulated as the percentof subjects choosing the cocaine lever.

Some bupropion analogues showed full generalization of the cocaine cuewith ED₅₀ values of 4.84 to 36.7 mg/kg in the initial cocainediscrimination study. Bupropion substituted only partially for thediscrimination stimulus effects of cocaine. The lowest dose yieldingmaximum substitution (10 mg/kg) resulted in 67% cocaine-appropriateresponding. However, response rate was increased relative to vehiclecontrol following 5-25 mg/kg. The N-cyclopropyl analogue 2x with partialgeneralization of 67% at 5 and 10 mg/kg also affected response rate at25-100 mg/kg similar to bupropion. The more potent DA uptake inhibitors2o-2q, which showed long durations of activity in the locomotor activitytest, all showed full generalization at 25 mg/kg.

All analogues tested in the time-course study (see Table 8, below)showed full generalization in at least one time point. ED₅₀ valuesranged from 5.36 to 52.4 mg/kg. Bupropion showed full generalization at45 min following a 50 mg/kg dose and partial generalization at 90 minafter a 50-mg/kg dose. The ED₅₀ for drug-appropriate responding 45 minfollowing bupropion was 23.2 mg/kg.

Analogue 2p showed partial generalization at 45 min following a 50 mg/kgdose, full generalization at 45 and 90 min, and partial generalizationat 180 min following a 100 mg/kg dose. Compound 2x showed partialgeneralization at 45 min following a 10-mg/kg and 25 mg/kg dose and fullgeneralization at 90 and 180 min at a 25 mg/kg dose.

Even though there was a general correlation between the IC₅₀ values forDA uptake and ED₅₀ values for cocaine generalization, there were severalexceptions. For example, the most potent analogue in the cocainediscrimination study was 2dd with an ED₅₀ value of 4.84 mg/kg. However,the IC₅₀ value for 2dd for DA uptake inhibitions was 1534 nM compared to943 nM for bupropion. Analogue 2j with an ED₅₀ value of 271 nM was3.5-times more potent as a DA uptake inhibitor than bupropion but didnot even show partial generalization.

In the time-course study, bupropion showed full generalization at 45 minfollowing a 50 mg/kg dose and partial generalization at 90 min after a50-mg/kg dose. The ED₅₀ for drug-appropriate responding 45 min followingbupropion was 23.2 mg/kg. Compound 2× showed only partial generalizationat 45 min (slower on-set) following a 10-mg/kg and 25-mg/kg dose andfull generalization at 90 and 180 min at a 25-mg/kg dose (longerlasting).

TABLE 7 Effect of Bupropion Analogues in Rats Trained to DiscriminateCocaine after IP Administration Dose (mg/kg), % cocaine Full leverresponding Generalization Compound 5 10 25 50 100 ED₅₀ (mg/kg)Comments^(a) Bupropion 0 67 66 A 2b 3 83 83 5.65 B 2c 1 0 50 10 10.76 B2d 1 27 83 11.4 B 2f 0 33 17 0 34 B 2g 1 17 17 0 B 2h 0 0 17 67 10 36.7C 2i 2 17 47 C 2j 0 17 34 2 B 2l 0 0 17 67 C 2m 17 50 83 17.93 B 2o 3 5010 8.23 C 2p 1 33 83 11.9 D 2q 1 67 10 8.17 E 2r 0 0 34 17 F 2s 0 0 4950 67 B 2u 0 0 70 B^(b) 2x 6 67 34 17 17 F 2z 2 0 66 83 10.8 H 2aa 1 1010 15.03 B 2bb 1 17 10 6.95 B 2cc 0 49 50 F 2dd 0 83 83 10 4.84 H 2ee 166 82 5.88 I 2ff 6 17 33 34 B ^(a)Response rate comments: A = Theaverage response rate was increased relative to vehicle controlfollowing 5 to 25 mg/kg, with a maximum effect at 5 mg/kg (127% ofvehicle control). The average response rate decreased to 30% of vehiclecontrol following 50 mg/kg bupropion. B = Response rate failed to showsignificant change. C = Response rate was reduced following 100 mg/kg. D= Response rate increased following 25 mg/kg. E = Response rate wasincreased following 5 mg/kg. F = Response rate was reduced following25-100 mg/kg. G = Response rate decreased following 50 and 100 mg/kg. H= Response rate was decreased following 25 mg/kg. I = Response rate wasdecreased following 10 and 25 mg/kg. ^(b)Adverse effects were seen at 50mg/kg.

TABLE 8 Drug Discrimination Effects of Bupropion and Bupropion Analoguesin Rats (p.o.) in a Time Course Study Pre-treatment Dose (mg/kg), %cocaine lever responding ED₅₀ Compound time 2.5 5 10 25 50 100 200(mg/kg) comments^(a) bupropion 45 0 0 0 50 83 23.2 A 90 0 0 0  0 50 1800 0 0 22 17 360 0 0 0  0  0 2b 45 6 0 0 51 83 25.6 A 90 1 0 0 33 33 1800 33 3 20 50 360 0 0 0 34  4 2c 45 17 17 49 66 95 27.1 B 90 0 0 16 33 75180 0 33  0 17 82 360 0 0  0  0 50 2d 45 13 0 0 17 51 67 100 52.4 C, D90 0 8 0  0 10 56 100 180 0 0 0  0  0 33 5 360 33 3 0  0  0 13 33 2m 450 16 0  4 67 18 43.6 E 90 20 7 33 25 58 84 180 0 0 0  0 20 17 360 0 0 2 7  0  0 2p 45 0 17 33 33^(b) 50^(c) 100^(d) 22.2 F 90 0 0 0 33^(b)17^(c) 100^(d) 180 0 11 17  0^(b) 17^(c)  50^(d) 360 0 0 2  0^(b) 16^(c) 1 2q 45 17 0  0 83 37.9 A 90 0 0  0 17 180 26 14  0 17 360 0 0  0  0 2s45 0  0 83 37.9 G 90 0  0 17 180 0  0 25 360 0  0  0 2x 45 17 17 57 6713.3 H 90 0 0 33 83 180 17 0 33 83 360 0 0 0  0 2z 45 11 50 51 67 838.28 A, I 90 50 0 17 67 83 180 0 0 0 67 34 360 0 0 0 34 16 22aa 45 33 1733 50 83 15.8 A 90 17 1 0 33 67 180 50 0 0  1 50 360 17 0 2 33 17 2bb 450 0 17 58 17.29 A 90 0 13 0 83 180 0 0 3 17 360 0 0 0  0 2dd 45 18 30 835.36 A 90 0 0 100 180 17 0 33 360 0 0 17 ^(a)Response rate comments: A =No significant change in response rate. B = Response rate was reduced at50 and 100 mg/kg. C = response rate was decreased at 200 mg/kg. D = Fourof 6 rats failed to complete the first fixed ratio at 180 min following200 mg/kg. E = Response rate was decreased 90 min following 50 mg/kg. F= Response rate was decreased following 2.5 and 5 mg/kg at 45 min. G =Response rate was increased relative to vehicle control 45 min following10 mg/kg of 2s. H = Response rate failed to show significant change as afunction of 2x at the 90-min pretreatment interval. Salivation wasobserved in 2/24 rats following 25 mg/kg of 2x. I = Decreased foodconsumption was observed following 25 mg/kg (1/24) rats and 50 mg/kg(1/24) rats. ^(b)Dose = 20 mg/kg. ^(c)Dose = 40 mg/kg. ^(d)Dose = 80mg/kg.

d) Overview of Biological Studies

In summary, bupropion analogues with better DAT binding (lower K_(i)values) and [³H]DA uptake (lower IC₅₀ values) were obtained by (a)replacing the methyl group a to the ketone group with medium-size alkylgroups; (b) changing the type and number of substituents on the3-chlorophenyl ring; and (c) replacing the N-tert-butyl group with otherN-alkyl groups. A number of bupropion analogues showed monoamineefficacy and an animal behavior profile that suggest they might bebetter indirect dopamine agonist than bupropion. Analogs 2o-2q and 2xhad the best overall profiles with 2x being the most interesting.Compound 2x was more potent than bupropion in the DA uptake inhibitiontest and was more selective for DA uptake relative to NE uptake thanbupropion. Unlike bupropion, 2x also has efficacy as a 5HT uptakeinhibitor. Studies from our laboratory as well as others have reportedanimal behavioral studies that show that reduction of cocaineself-administration can be enhanced by 5HT uptake inhibition. Theactivity of 2x in an initial drug discrimination study is very similarto that of bupropion. More importantly, 2x was more potent thanbupropion in the time-course discrimination study and had a sloweron-set and longer duration of action. The in vitro efficacy and animalbehavioral properties thought to be necessary for an indirect dopamineagonist pharmacotherapy for treating abuse of cocaine, methamphetamine,and nicotine are both better for 2x than for bupropion.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims.Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

That which is claimed:
 1. A compound according to the structure:

wherein: R₁-R₅ are each independently selected from H, OH, substitutedor unsubstituted C1-4 alkyl, substituted or unsubstituted C1-3 alkoxy,substituted or unsubstituted C2-4 alkenyl, substituted or unsubstitutedC2-4 alkynyl, halo, amino, acylamido, CN, CF₃, NO₂, N₃, CONH₂, CO₂R₁₂,CH₂OR₁₂, NR₁₂R₁₃, NHCOR₁₂, NHCO₂R₁₂, CONR₁₂R₁₃; C1-3 alkylthio, R₁₂SO,R₁₂SO₂, CF₃S, and CF₃SO₂; R₈ is H or substituted or unsubstituted C1-10alkyl; R₉ is substituted or unsubstituted C2-C7 alkyl; R₁₂ and R₁₃ areeach independently H or substituted or unsubstituted C1-10 alkyl; andwherein R₁ and R₈ may be joined to form a cyclic ring; or apharmaceutically acceptable ester, amide, salt, solvate, or stereoisomerthereof.
 2. The compound according to claim 1, wherein one or more ofR₁, R₂, R₃, R₄, and R₅ is a substituent other than H.
 3. The compoundaccording to claim 2, wherein the substituent comprises halo.
 4. Thecompound according to claim 3, wherein the halo is chloro.
 5. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.